49 results on '"Sang-Bae Kim"'
Search Results
2. Corrigendum: FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair
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Sang Bae Kim, Nicholas B. Jennings, Ju Seog Lee, Sun Hee Leem, Guang Peng, Gabriel Lopez-Berestein, Se Ra Lee, Kyounghyun Kim, Cristian Rodriguez-Aguayo, Yun Yong Park, Shiaw Yih Lin, Anil K. Sood, and Sung Yun Jung
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Cancer Research ,DNA Repair ,DNA repair ,Transplantation, Heterologous ,Breast Neoplasms ,Mice, Transgenic ,Mice ,Breast cancer ,Cell Line, Tumor ,medicine ,Animals ,Humans ,business.industry ,NF-kappa B p50 Subunit ,Forkhead Transcription Factors ,General Medicine ,medicine.disease ,Prognosis ,Gene Expression Regulation, Neoplastic ,Drug Resistance, Neoplasm ,FOXM1 ,Cancer research ,Female ,business ,Corrigendum ,Transcription Factors - Abstract
Transcription factors are direct effectors of altered signaling pathways in cancer and frequently determine clinical outcomes in cancer patients. To uncover new transcription factors that would determine clinical outcomes in breast cancer, we systematically analyzed gene expression data from breast cancer patients. Our results revealed that Forkhead box protein M1 (FOXM1) is the top-ranked survival-associated transcription factor in patients with triple-negative breast cancer. Surprisingly, silencing FOXM1 expression led breast cancer cells to become more sensitive to doxorubicin (Dox). We found that FOXM1-dependent resistance to Dox is mediated by regulating DNA repair genes. We further demonstrated that NFκB1 interacts with FOXM1 in the presence of Dox to protect breast cancer cells from DNA damage. Finally, silencing FOXM1 expression in breast cancer cells in a mouse xenograft model significantly sensitized the cells to Dox. Our systematic approaches identified an unexpected role of FOXM1 in Dox resistance by regulating DNA repair genes, and our findings provide mechanistic insights into how FOXM1 mediates resistance to Dox and evidence that FOXM1 may be a promising therapeutic target for sensitizing breast cancer cells to Dox.
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- 2019
3. Integrated genomic analysis of recurrence-associated small non-coding RNAs in oesophageal cancer
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Hee Jin Jang, Sang Bae Kim, Bryan M. Burt, Sang Cheol Kim, Jae Ill Zo, Yoon-La Choi, David J. Sugarbaker, Seon-Young Kim, Kyong Ah Yoon, Duncan Mak, Jungnam Joo, Kook Joo Na, Moon Soo Kim, Leng Han, Jared K. Burks, Jong Lyul Park, Geon Kook Lee, Yong Sun Lee, Ju Sik Yun, Bo Hwa Sohn, Young Mog Shim, Ju Seog Lee, Yun Yong Park, Hyun-Sung Lee, Jong Mog Lee, and Han Liang
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Adult ,Male ,0301 basic medicine ,Esophageal Neoplasms ,Class I Phosphatidylinositol 3-Kinases ,Antineoplastic Agents ,Apoptosis ,Cell Cycle Proteins ,Disease ,Protein Serine-Threonine Kinases ,Biology ,Bioinformatics ,Models, Biological ,Risk Assessment ,Disease-Free Survival ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Surgical oncology ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Gene expression ,microRNA ,medicine ,Humans ,Molecular Targeted Therapy ,PI3K/AKT/mTOR pathway ,Aged ,Aged, 80 and over ,Systems Biology ,TOR Serine-Threonine Kinases ,Tumor Suppressor Proteins ,Gastroenterology ,Cancer ,Genomics ,Middle Aged ,medicine.disease ,Histone Deacetylase Inhibitors ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,Carcinoma, Squamous Cell ,Female ,Histone deacetylase ,Drug Screening Assays, Antitumor ,Neoplasm Recurrence, Local ,Transcription Factors - Abstract
Objective Oesophageal squamous cell carcinoma (ESCC) is a heterogeneous disease with variable outcomes that are challenging to predict. A better understanding of the biology of ESCC recurrence is needed to improve patient care. Our goal was to identify small non-coding RNAs (sncRNAs) that could predict the likelihood of recurrence after surgical resection and to uncover potential molecular mechanisms that dictate clinical heterogeneity. Design We developed a robust prediction model for recurrence based on the analysis of the expression profile data of sncRNAs from 108 fresh frozen ESCC specimens as a discovery set and assessment of the associations between sncRNAs and recurrence-free survival (RFS). We also evaluated the mechanistic and therapeutic implications of sncRNA obtained through integrated analysis from multiple datasets. Results We developed a risk assessment score (RAS) for recurrence with three sncRNAs (microRNA (miR)-223, miR-1269a and nc886) whose expression was significantly associated with RFS in the discovery cohort (n=108). RAS was validated in an independent cohort of 512 patients. In multivariable analysis, RAS was an independent predictor of recurrence (HR, 2.27; 95% CI, 1.26 to 4.09; p=0 . 007). This signature implies the expression of ΔNp63 and multiple alterations of driver genes like PIK3CA. We suggested therapeutic potentials of immune checkpoint inhibitors in low-risk patients, and Polo-like kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase inhibitors in high-risk patients. Conclusion We developed an easy-to-use prognostic model with three sncRNAs as robust prognostic markers for postoperative recurrence of ESCC. We anticipate that such a stratified and systematic, tumour-specific biological approach will potentially contribute to significant improvement in ESCC treatment.
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- 2016
4. Predictive Value of Antiviral Effects in the Development of Hepatocellular Carcinoma in the General Korean Population with Chronic Hepatitis B
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Jung-Wook Kim, Chang Kyun Lee, Sang Bae Kim, Byung Ho Kim, Ju Seog Lee, In-Hwan Oh, Jae Young Jang, and Jae-Jun Shim
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Adult ,Male ,medicine.medical_specialty ,Hepatitis B virus ,Carcinoma, Hepatocellular ,National Health and Nutrition Examination Survey ,Population ,Antiviral therapy ,Gastroenterology ,Antiviral Agents ,Risk Assessment ,Virus ,03 medical and health sciences ,0302 clinical medicine ,hepatocellular ,Hepatitis B, Chronic ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,Republic of Korea ,Carcinoma ,medicine ,Humans ,education ,Transaminases ,education.field_of_study ,Hepatology ,business.industry ,Korean population ,Liver Neoplasms ,Hepatitis B ,Middle Aged ,medicine.disease ,Nutrition Surveys ,digestive system diseases ,chronic ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cohort ,DNA, Viral ,030211 gastroenterology & hepatology ,Original Article ,Female ,business - Abstract
Background/Aims: The benefit of oral antiviral therapy in preventing hepatocellular carcinoma (HCC) in the general population is not well understood. We used a novel prediction method to estimate the risk of HCC in the Korean population based on various treatment guidelines. Methods: The 5-year risk of HCC following antiviral therapy was calculated using an HCC risk prediction model. A virtual cohort that represented Koreans (>40 years old) with chronic hepatitis B virus (HBV) infection was established using the fifth National Health and Nutrition Examination Survey. The antiviral indications tested were the Korean National Health Insurance (NHI) and European Association for the Study of the Liver (EASL) guidelines as well as a new extended indication (serum HBV DNA >2,000 IU/mL regardless of serum aminotransferase level). Results: A total of 993,872 subjects were infected with HBV in the general Korean population. Over a 5-year period, 2,725 HCC cases were predicted per 100,000 persons (0.55%/yr). When the cohort was treated based on the Korean NHI, the EASL, and the newly extended indications, HCC risks decreased to 2,531 (-7.1%), 2,089 (-23.3%), and 1,122 (-58.8%) cases per 100,000 persons, respectively (p
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- 2016
5. Integrated Genomic Comparison of Mouse Models Reveals Their Clinical Resemblance to Human Liver Cancer
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Randy L. Johnson, Snorri S. Thorgeirsson, Valentina M. Factor, Ju Seog Lee, Dong Jin Lee, Elizabeth A. Conner, David D. Moore, Sang Bae Kim, Sun Young Yim, Jae-Jun Shim, Yun Seong Jeong, Young-Gyu Eun, Sanghee Kang, and Ji Hyun Shin
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0301 basic medicine ,Cancer Research ,TGF alpha ,medicine.medical_treatment ,Transgenic Model ,Mice ,0302 clinical medicine ,Liver Neoplasms, Experimental ,2.1 Biological and endogenous factors ,Aetiology ,Cancer ,Liver Disease ,Liver Neoplasms ,Genomics ,Prognosis ,Oncology ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Experimental pathology ,Development of treatments and therapeutic interventions ,Biotechnology ,Liver Cancer ,Carcinoma, Hepatocellular ,Oncology and Carcinogenesis ,Biology ,Article ,03 medical and health sciences ,Experimental ,Rare Diseases ,medicine ,Genetics ,Animals ,Humans ,Oncology & Carcinogenesis ,Molecular Biology ,CD86 ,Animal ,Carcinoma ,Human Genome ,Hepatocellular ,Immunotherapy ,HCCS ,medicine.disease ,digestive system diseases ,Disease Models, Animal ,030104 developmental biology ,Orphan Drug ,Good Health and Well Being ,Disease Models ,Cancer research ,Digestive Diseases ,Developmental Biology - Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous disease. Mouse models are commonly used as preclinical models to study hepatocarcinogenesis, but how well these models recapitulate molecular subtypes of human HCC is unclear. Here, integration of genomic signatures from molecularly and clinically defined human HCC (n = 11) and mouse models of HCC (n = 9) identified the mouse models that best resembled subtypes of human HCC and determined the clinical relevance of each model. Mst1/2 knockout (KO), Sav1 KO, and SV40 T antigen mouse models effectively recapitulated subtypes of human HCC with a poor prognosis, whereas the Myc transgenic model best resembled human HCCs with a more favorable prognosis. The Myc model was also associated with activation of β-catenin. E2f1, E2f1/Myc, E2f1/Tgfa, and diethylnitrosamine (DEN)-induced models were heterogeneous and were unequally split into poor and favorable prognoses. Mst1/2 KO and Sav1 KO models best resemble human HCC with hepatic stem cell characteristics. Applying a genomic predictor for immunotherapy, the six-gene IFNγ score, the Mst1/2 KO, Sav1 KO, SV40, and DEN models were predicted to be the least responsive to immunotherapy. Further analysis showed that elevated expression of immune-inhibitory genes (Cd276 and Nectin2/Pvrl2) in Mst1/2 KO, Sav1 KO, and SV40 models and decreased expression of immune stimulatory gene (Cd86) in the DEN model might be accountable for the lack of predictive response to immunotherapy. Implication: The current genomic approach identified the most relevant mouse models to human liver cancer and suggests immunotherapeutic potential for the treatment of specific subtypes. Mol Cancer Res; 16(11); 1713–23. ©2018 AACR.
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- 2018
6. Clinical and genomic landscape of gastric cancer with a mesenchymal phenotype
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Jeonghoon Heo, You Jin Jang, Jong Lyul Park, In Sun Chu, Yuki Hayashi, Elena Elimova, Hyun-Sung Lee, Wonkyung Jung, Manoop S. Bhutani, Jae Eun Lee, Jeeyun Lee, Yiling Lu, Eun Sung Park, Gordon B. Mills, Wenbin Liu, Sung Hoon Noh, Aeree Kim, Sangho Lee, Young Jae Mok, Jeannelyn S. Estralla, Ki Cheong Park, Jeffrey H. Lee, Jaffer A. Ajani, Sang Cheul Oh, Bo Hwa Sohn, Sang Bae Kim, Jae Yong Cho, Yun Yong Park, Shumei Song, Sang Cheol Kim, Won Ki Kang, Seon-Young Kim, Baek Hui Kim, Jae Yun Lim, Hee Jin Jang, Jae Ho Cheong, Ju Seog Lee, and Sung Kim
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Proteomics ,0301 basic medicine ,General Physics and Astronomy ,Kaplan-Meier Estimate ,medicine.disease_cause ,Receptor, IGF Type 1 ,Mesoderm ,Transcriptome ,0302 clinical medicine ,lcsh:Science ,Mice, Inbred BALB C ,Mutation ,Multidisciplinary ,Genomics ,Prognosis ,3. Good health ,Gene Expression Regulation, Neoplastic ,Phenotype ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Heterografts ,Female ,Microsatellite Instability ,Signal Transduction ,Epithelial-Mesenchymal Transition ,Gastrointestinal Stromal Tumors ,Science ,Antineoplastic Agents ,Adenocarcinoma ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Stomach Neoplasms ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Gastrointestinal cancer ,Epithelial–mesenchymal transition ,Insulin-like growth factor 1 receptor ,Reproducibility of Results ,Microsatellite instability ,Cancer ,General Chemistry ,medicine.disease ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cancer cell ,Cancer research ,lcsh:Q - Abstract
Gastric cancer is a heterogeneous cancer, making treatment responses difficult to predict. Here we show that we identify two distinct molecular subtypes, mesenchymal phenotype (MP) and epithelial phenotype (EP), by analyzing genomic and proteomic data. Molecularly, MP subtype tumors show high genomic integrity characterized by low mutation rates and microsatellite stability, whereas EP subtype tumors show low genomic integrity. Clinically, the MP subtype is associated with markedly poor survival and resistance to standard chemotherapy, whereas the EP subtype is associated with better survival rates and sensitivity to chemotherapy. Integrative analysis shows that signaling pathways driving epithelial-to-mesenchymal transition and insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R) pathway are highly activated in MP subtype tumors. Importantly, MP subtype cancer cells are more sensitive to inhibition of IGF1/IGF1R pathway than EP subtype. Detailed characterization of these two subtypes could identify novel therapeutic targets and useful biomarkers for prognosis and therapy response., The prognosis and treatment of gastric cancer is complicated by heterogeneity. Here, the authors reveal two molecular subtypes, the mesenchymal subtype associated with poor survival and chemoresistance, and the epithelial phenotype associated with better survival and sensitivity to chemotherapy.
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- 2018
7. Effects of Aerobic Exercise on PGC-1α, AMPK and SOD Expression of Skeletal Muscle in 2Type Diabetic Rats
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김대성 ( Dae Sung Kim ), Jin hwan Yoon, JongOh Kim, and 김상배 ( Sang Bae Kim )
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medicine.medical_specialty ,business.industry ,Public Health, Environmental and Occupational Health ,AMPK ,Skeletal muscle ,Physical Therapy, Sports Therapy and Rehabilitation ,Treadmill exercise ,Mitochondrion ,medicine.disease ,Endocrinology ,Insulin resistance ,medicine.anatomical_structure ,Physiology (medical) ,Internal medicine ,medicine ,Aerobic exercise ,Exercise physiology ,business - Published
- 2015
8. Genomic landscape associated with potential response to anti-CTLA-4 treatment in cancers
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Jae-Jun Shim, Tae Min Kim, Bhumsuk Keam, Minse Cha, Sang Bae Kim, Jaffer A. Ajani, Bo Hwa Sohn, Ju Seog Lee, Scott Kopetz, Keun Wook Lee, Sarang Park, Hee Jin Jang, Chan Young Ock, Jun Eul Hwang, and Dae Seog Heo
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Genetic Markers ,0301 basic medicine ,Science ,medicine.medical_treatment ,Gene Dosage ,Gene Expression ,General Physics and Astronomy ,Genomics ,medicine.disease_cause ,Gene dosage ,Antibodies ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,Cancer immunotherapy ,Neoplasms ,medicine ,Animals ,Humans ,CTLA-4 Antigen ,lcsh:Science ,Mutation ,Multidisciplinary ,biology ,Cancer ,General Chemistry ,Immunotherapy ,medicine.disease ,3. Good health ,Clinical trial ,Treatment Outcome ,030104 developmental biology ,biology.protein ,Cancer research ,lcsh:Q ,Antibody - Abstract
Immunotherapy has emerged as a promising anti-cancer treatment, however, little is known about the genetic characteristics that dictate response to immunotherapy. We develop a transcriptional predictor of immunotherapy response and assess its prediction in genomic data from ~10,000 human tissues across 30 different cancer types to estimate the potential response to immunotherapy. The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it. We identify somatic mutations and copy number alterations significantly associated with potential response to immunotherapy, in particular treatment with anti-CTLA-4 antibody. Our findings suggest that tumors may evolve through two different paths that would lead to marked differences in immunotherapy response as well as different strategies for evading immune surveillance. Our analysis provides resources to facilitate the discovery of predictive biomarkers for immunotherapy that could be tested in clinical trials., There is an urgent need to identify predictive markers for selecting responders to immunotherapy. Here, the authors describe a transcriptional predictor of immunotherapy response and assess it in genomic data from ~ 10,000 human tissues across 30 different cancer types.
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- 2017
9. Molecular Profiling of Patient-Matched Brain and Extracranial Melanoma Metastases Implicates the PI3K Pathway as a Therapeutic Target
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Michael A. Davies, Y.N. Vashisht Gopal, Victor G. Prieto, Alicia Ledoux, Darrin Stuart, Scott Kopetz, Cristiano Gonçalves Pereira, Nitin Chakravarti, Kenneth Aldape, Katherine L. Nathanson, Ju Seog Lee, Wanleng Deng, Alexander J. Lazar, Michael T. Tetzlaff, Guo Chen, Kimberly Aardalen, Bradley Wubbenhorst, and Sang Bae Kim
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Proto-Oncogene Proteins B-raf ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,DNA Copy Number Variations ,Disease ,Biology ,Bioinformatics ,Article ,GTP Phosphohydrolases ,Phosphatidylinositol 3-Kinases ,Paired samples ,medicine ,Humans ,RNA, Messenger ,Copy-number variation ,Neoplasm Metastasis ,Melanoma ,PI3K/AKT/mTOR pathway ,Brain Neoplasms ,Brain ,Membrane Proteins ,medicine.disease ,Oncology ,Mutation ,Cancer research ,Protein microarray ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Purpose: An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches. Experimental Design: Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and quantitative analysis of protein expression and activation by reverse-phase protein array (RPPA) analysis were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors. Results: The status of 154 previously reported hotspot mutations, including driver mutations in BRAF and NRAS, were concordant in all evaluable patient-matched pairs of tumors. Overall patterns of CNV, mRNA expression, and protein expression were largely similar between the paired samples for individual patients. However, brain metastases demonstrated increased expression of several activation-specific protein markers in the PI3K/AKT pathway compared with the extracranial metastases. Conclusions: These results add to the understanding of the molecular characteristics of melanoma brain metastases and support the rationale for additional testing of the PI3K/AKT pathway as a therapeutic target in these highly aggressive tumors. Clin Cancer Res; 20(21); 5537–46. ©2014 AACR.
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- 2014
10. Wnt pathway contributes to the protection by bone marrow stromal cells of acute lymphoblastic leukemia cells and is a potential therapeutic target
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Jing Zhang, Zhen Cai, Xiaoping Sun, Saradhi Mallampati, Ju Seog Lee, Yun Gong, Baohua Sun, Sang Bae Kim, and Yang Yang
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Cancer Research ,Stromal cell ,medicine.medical_treatment ,Apoptosis ,Mice, SCID ,Biology ,Article ,Mice ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Wnt Signaling Pathway ,beta Catenin ,Regulation of gene expression ,Chemotherapy ,Gene Expression Regulation, Leukemic ,Cell Cycle ,Mesenchymal stem cell ,Cytarabine ,Wnt signaling pathway ,Mesenchymal Stem Cells ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Cell cycle ,medicine.disease ,Leukemia ,medicine.anatomical_structure ,Oncology ,Immunology ,Cancer research ,Bone marrow ,Heterocyclic Compounds, 3-Ring - Abstract
Leukemia cells are protected by various components of their microenvironment, including marrow stromal cells (MSCs). To understand the molecular mechanisms underlying this protection, we cultured acute lymphoblastic leukemia (ALL) cells with MSCs and studied the effect of the latter on the molecular profiling of ALL cells at the mRNA and protein levels. Our results indicated that activated Wnt signaling in ALL cells is involved in MSC-mediated drug resistance. Blocking the Wnt pathway sensitized the leukemia cells to chemotherapy and improved overall survival in a mouse model. Targeting the Wnt pathway may be an innovative approach to the treatment of ALL.
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- 2013
11. Vitamin D Deficiency Promotes Liver Tumor Growth in Transforming Growth Factor-β/Smad3-Deficient Mice Through Wnt and Toll-like Receptor 7 Pathway Modulation
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Shulin Li, Lior H. Katz, Asif Rashid, Kirti Shetty, Jaclyn Andricovich, Wilma Jogunoori, Mitchell Belkin, Shoujun Gu, Sang Soo Kim, Nina M. Muñoz, Ju Seog Lee, Mi Hye Lee, Alexandros Tzatsos, Jon White, Sang Bae Kim, Jian Chen, Lopa Mishra, Bibhuti Mishra, and Ji Hyun Shin
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0301 basic medicine ,Male ,medicine.medical_specialty ,Liver tumor ,Transgene ,Context (language use) ,Mice, Transgenic ,vitamin D deficiency ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Liver Neoplasms, Experimental ,Transforming Growth Factor beta ,Internal medicine ,medicine ,Animals ,Humans ,Smad3 Protein ,Vitamin D ,Multidisciplinary ,Membrane Glycoproteins ,biology ,Wnt signaling pathway ,Transforming growth factor beta ,medicine.disease ,Vitamin D Deficiency ,3. Good health ,Wnt Proteins ,030104 developmental biology ,Endocrinology ,Toll-Like Receptor 7 ,030220 oncology & carcinogenesis ,biology.protein ,Signal transduction ,Transforming growth factor ,Signal Transduction - Abstract
Disruption of the TGF-β pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-β signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3+/− mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-β pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-β pathway member expression levels and β-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-β member expression with lower β-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-β pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and β-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling.
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- 2016
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12. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer
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Stephen Safe, Greg A. Johnson, Robert C. Burghardt, Indira Jutooru, James H. Frank, Kyounghyun Kim, Sang Bae Kim, and Gayathri Chadalapaka
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Cancer Research ,Transplantation, Heterologous ,Biology ,pro-oncogenic ,Article ,Mice ,03 medical and health sciences ,HOTAIR ,0302 clinical medicine ,RNA interference ,Cell Line, Tumor ,Pancreatic cancer ,Biomarkers, Tumor ,Genetics ,Gene Knockdown Techniques ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Molecular Biology ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Gene knockdown ,cell cycle progression ,Cell growth ,EZH2 ,invasion ,Prognosis ,medicine.disease ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,Cell Transformation, Neoplastic ,030220 oncology & carcinogenesis ,Cancer research ,Female ,RNA, Long Noncoding ,prognostic ,HOX Transcript Antisense RNA ,Carcinoma, Pancreatic Ductal - Abstract
HOTAIR is a long intervening non-coding RNA (lincRNA) that associates with the Polycomb Repressive Complex 2 (PRC2) and overexpression is correlated with poor survival for breast, colon and liver cancer patients. In this study, we show that HOTAIR expression is increased in pancreatic tumors compared with non-tumor tissue and is associated with more aggressive tumors. Knockdown of HOTAIR (siHOTAIR) by RNA interference shows that HOTAIR has an important role in pancreatic cancer cell invasion, as reported in other cancer cell lines. In contrast, HOTAIR knockdown in Panc1 and L3.6pL pancreatic cancer cells that overexpress this lincRNA decreased cell proliferation, altered cell cycle progression and induced apoptosis, demonstrating an expanded function of HOTAIR in pancreatic cancer cells compared with other cancer cell lines. Results of gene array studies showed that there was minimal overlap between HOTAIR-regulated genes in pancreatic cells and breast cancer cells, and HOTAIR uniquely suppressed several interferon-related genes and gene sets related to cell cycle progression in pancreatic cancer cells and tumors. Analysis of selected genes suppressed by HOTAIR in Panc1 and L3.6pL cells showed by knockdown of EZH2 and chromatin immunoprecipitation assays that HOTAIR-mediated gene repression was both PRC2-dependent and -independent. HOTAIR knockdown in L3.6pL cells inhibited tumor growth in mouse xenograft model, further demonstrating the pro-oncogenic function of HOTAIR in pancreatic cancer.
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- 2012
13. Development and Validation of a Six-Gene Recurrence Risk Score Assay for Gastric Cancer
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Sung Sook Lee, Sang Cheul Oh, Woojin Jeong, Sang Bae Kim, Hyun-Sung Lee, Jae Yong Cho, Sang Cheol Kim, Keun Wook Lee, Yoon-Koo Kang, Bo Hwa Sohn, Sung Hoon Noh, Jae Yun Lim, Sangho Lee, Jae Ho Cheong, Jae-Jun Shim, Ju Seog Lee, Jun Eul Hwang, Eun Sung Park, Hee Jin Jang, Minse Cha, and Jaffer A. Ajani
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0301 basic medicine ,Oncology ,Adult ,Male ,Risk ,Cancer Research ,medicine.medical_specialty ,Gene Expression ,Bioinformatics ,Disease-Free Survival ,Article ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,Internal medicine ,medicine ,Humans ,Gastrointestinal cancer ,Prospective cohort study ,Aged ,Aged, 80 and over ,Oncogene ,business.industry ,Gene Expression Profiling ,Hazard ratio ,Cancer ,Middle Aged ,medicine.disease ,Prognosis ,Confidence interval ,Reverse transcription polymerase chain reaction ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,Female ,Neoplasm Recurrence, Local ,business - Abstract
Purpose: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery. Experimental Design: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n = 267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P < 0.001). We developed the recurrence risk score (RRS) by using quantitative RT-PCR to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort. Results: We based the RRS assay on 6 genes, IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B, whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort. The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence [HR, 1.6; 95% confidence interval (CI), 1.02–2.4; P = 0.03]. In patients with stage II disease, the RRS had an HR of 2.9 (95% CI, 1.1–7.9; P = 0.03) and was the only significant independent predictor of recurrence. Conclusions: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted. Clin Cancer Res; 22(24); 6228–35. ©2016 AACR.
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- 2015
14. Prognostic gene expression signature associated with two molecularly distinct subtypes of colorectal cancer
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Timothy J. Yeatman, J. Joshua Smith, Soo Mi Kim, Ju Seog Lee, Eun Sung Park, Jong Seung Kim, Sang Cheol Kim, R. Daniel Beauchamp, Yun Yong Park, Scott Kopetz, Sang Cheul Oh, In Sun Chu, Sang Bae Kim, and Jae Yun Lim
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Adult ,Male ,Subset Analysis ,Oncology ,medicine.medical_specialty ,Colorectal cancer ,Antineoplastic Agents ,Kaplan-Meier Estimate ,Article ,Cohort Studies ,Young Adult ,Internal medicine ,Cluster Analysis ,Humans ,Medicine ,Risk factor ,Survival rate ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Proportional hazards model ,business.industry ,Gene Expression Profiling ,Gastroenterology ,Cancer ,Middle Aged ,Gene signature ,Prognosis ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Gene expression profiling ,Treatment Outcome ,Chemotherapy, Adjuvant ,Immunology ,Female ,Colorectal Neoplasms ,business - Abstract
Aims Despite continual efforts to develop prognostic and predictive models of colorectal cancer by using clinicopathological and genetic parameters, a clinical test that can discriminate between patients with good or poor outcome after treatment has not been established. Thus, the authors aim to uncover subtypes of colorectal cancer that have distinct biological characteristics associated with prognosis and identify potential biomarkers that best reflect the biological and clinical characteristics of subtypes. Methods Unsupervised hierarchical clustering analysis was applied to gene expression data from 177 patients with colorectal cancer to determine a prognostic gene expression signature. Validation of the signature was sought in two independent patient groups. The association between the signature and prognosis of patients was assessed by Kaplan–Meier plots, log-rank tests and the Cox model. Results The authors identified a gene signature that was associated with overall survival and disease-free survival in 177 patients and validated in two independent cohorts of 213 patients. In multivariate analysis, the signature was an independent risk factor (HR 3.08; 95% CI 1.33 to 7.14; p=0.008 for overall survival). Subset analysis of patients with AJCC (American Joint Committee on Cancer) stage III cancer revealed that the signature can also identify the patients who have better outcome with adjuvant chemotherapy (CTX). Adjuvant chemotherapy significantly affected disease-free survival in patients in subtype B (3-year rate, 71.2% (CTX) vs 41.9% (no CTX); p=0.004). However, such benefit of adjuvant chemotherapy was not significant for patients in subtype A. Conclusion The gene signature is an independent predictor of response to chemotherapy and clinical outcome in patients with colorectal cancer.
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- 2011
15. Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis
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Gordon B. Mills, Sun Jin Kim, Isaiah J. Fidler, Ju Seog Lee, Sang Bae Kim, Se Lyun Yoon, Soo Mi Kim, Yun Yong Park, Eun Sung Park, Hyun Goo Woo, Seung Wook Kim, Sun Hee Leem, and Jae Ho Cheong
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Male ,Stromal cell ,Transplantation, Heterologous ,Mice, Nude ,Biology ,Epigenesis, Genetic ,Metastasis ,Transcriptome ,Mice ,Species Specificity ,Cancer stem cell ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Humans ,DNA Primers ,Oligonucleotide Array Sequence Analysis ,Neurons ,Mice, Inbred BALB C ,Tumor microenvironment ,Multidisciplinary ,Base Sequence ,Brain Neoplasms ,Nucleic Acid Hybridization ,Cancer ,DNA, Neoplasm ,DNA Methylation ,Biological Sciences ,medicine.disease ,Molecular biology ,Coculture Techniques ,Cell biology ,Astrocytes ,Cancer cell ,Reprogramming ,Neoplasm Transplantation - Abstract
Although the importance of the cellular microenvironment (soil) during invasion and metastasis of cancer cells (seed) has been well-recognized, technical challenges have limited the ability to assess the influence of the microenvironment on cancer cells at the molecular level. Here, we show that an experimental strategy, competitive cross-species hybridization of microarray experiments, can characterize the influence of different microenvironments on cancer cells by independently extracting gene expression data of cancer and host cells when human cancer cells were xenografted into different organ sites of immunocompromised mice. Surprisingly, the analysis of gene expression data showed that the brain microenvironment induces complete reprogramming of metastasized cancer cells, resulting in a gain of neuronal cell characteristics and mimicking neurogenesis during development. We also show that epigenetic changes coincide with transcriptional reprogramming in cancer cells. These observations provide proof of principle for competitive cross-species hybridization of microarray experiments to characterize the effect of the microenvironment on tumor cell behavior.
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- 2011
16. Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer
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Meenhard Herlyn, Christie M. Gutierrez, Gabrielle S. Wong, J. Alan Diehl, Carmen Z. Michaylira, Rachel Hammond, Ju Seog Lee, Phyllis A. Gimotty, Andres J. Klein-Szanto, Sang Bae Kim, Anil K. Rustgi, Hiroshi Nakagawa, and Charles G. Miller
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Cancer Research ,Pathology ,medicine.medical_specialty ,Esophageal Neoplasms ,Tumor suppressor gene ,Periostin ,Article ,Metastasis ,Tumor Cells, Cultured ,medicine ,Humans ,Neoplasm Invasiveness ,Epidermal growth factor receptor ,Telomerase ,Tumor microenvironment ,biology ,Cell adhesion molecule ,Gene Expression Profiling ,Cancer ,medicine.disease ,ErbB Receptors ,Gene expression profiling ,Oncology ,Carcinoma, Squamous Cell ,Cancer research ,biology.protein ,Tumor Suppressor Protein p53 ,Cell Adhesion Molecules - Abstract
Human squamous cell cancers are the most common epithelially derived malignancies. One example is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate that is related to a propensity for invasion and metastasis. Here, we report that periostin, a highly expressed cell adhesion molecule, is a key component of a novel tumor-invasive signature obtained from an organotypic culture model of engineered ESCC. This tumor-invasive signature classifies with human ESCC microarrays, underscoring its utility in human cancer. Genetic modulation of periostin promotes tumor cell migration and invasion as revealed in gain-of-loss and loss-of-function experiments. Inhibition of epidermal growth factor receptor signaling and restoration of wild-type p53 function were each found to attenuate periostin, suggesting the interdependence of two common genetic alterations with periostin function. Collectively, our studies reveal periostin as an important mediator of ESCC tumor invasion and they indicate that organotypic (three-dimensional) culture can offer an important tool to discover novel biological effectors in cancer. Cancer Res; 70(13); 5281–92. ©2010 AACR.
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- 2010
17. Inactivation of Hippo Pathway Is Significantly Associated with Poor Prognosis in Hepatocellular Carcinoma
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Jeonghoon Heo, Randy L. Johnson, Yun Yong Park, Ahmed Kaseb, Soo Mi Kim, Jun Eul Hwang, Eun Sung Park, Sun Hee Leem, Hee Jin Jang, Yoon Jun Kim, Hyun-Sung Lee, Kyu Yun Jang, Sung Soo Kim, Manal M. Hassan, Minse Cha, Ju Seog Lee, Bo Hwa Sohn, In Sun Chu, Ji Hoon Kim, Sang Bae Kim, Sang Cheol Kim, Dae Ghon Kim, Jae-Jun Shim, and Woojin Jeong
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0301 basic medicine ,Adult ,Male ,Cancer Research ,MST1 ,Carcinoma, Hepatocellular ,Kaplan-Meier Estimate ,Protein Serine-Threonine Kinases ,Bioinformatics ,Disease-Free Survival ,Article ,03 medical and health sciences ,Mice ,Cell Line, Tumor ,Gene expression ,Carcinoma ,Biomarkers, Tumor ,Medicine ,Animals ,Humans ,Clinical significance ,Hippo Signaling Pathway ,Adaptor Proteins, Signal Transducing ,Aged ,Regulation of gene expression ,Aged, 80 and over ,Hippo signaling pathway ,business.industry ,Liver Neoplasms ,Intracellular Signaling Peptides and Proteins ,Cancer ,YAP-Signaling Proteins ,Middle Aged ,medicine.disease ,Phosphoproteins ,Prognosis ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Hepatocellular carcinoma ,Transcriptional Coactivator with PDZ-Binding Motif Proteins ,Cancer research ,Trans-Activators ,Female ,business ,Signal Transduction ,Transcription Factors - Abstract
Purpose: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC. Experimental Design: We analyzed gene expression data from Mst1/2−/− and Sav1−/− mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses. Results: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12–2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001). Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis. Clin Cancer Res; 22(5); 1256–64. ©2015 AACR.
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- 2015
18. Omeprazole Inhibits Pancreatic Cancer Cell Invasion Through a Non-genomic Aryl Hydrocarbon Receptor Pathway
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Sang Bae Kim, Stephen Safe, and Un Ho Jin
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Aryl hydrocarbon receptor nuclear translocator ,Tranilast ,Antineoplastic Agents ,Pharmacology ,Biology ,Toxicology ,Article ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Cytochrome P-450 CYP1A1 ,Humans ,Neoplasm Invasiveness ,Receptor ,Pancreas ,General Medicine ,respiratory system ,Aryl hydrocarbon receptor ,medicine.disease ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Receptors, Aryl Hydrocarbon ,Cell culture ,biology.protein ,Female ,Signal transduction ,Omeprazole ,medicine.drug ,Signal Transduction - Abstract
Omeprazole and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are aryl hydrocarbon receptor (AhR) agonist that inhibit invasion of breast cancer cell through inhibition of CXCR4 transcription. Treatment of highly invasive Panc1 pancreatic cancer cells with TCDD, omeprazole and seven other AhR-active pharmaceuticals showed that only omeprazole and tranilast but not TCDD inhibited invasion in a Boyden chamber assay. Similar results were observed in MiaPaCa2 cells, another quasimensenchymal pancreatic ductal adenocarcinoma (QM-PDA) pancreatic cancer cell line, whereas invasion was not observed in BxPC3 or L3.6pL cells which are classified as “classical” (less invasive) pancreatic cancer cells. It was also observed that in the QM-PDA cells that TCDD, omeprazole and tranilast did not induce CYP1A1 or CXCR4 and treatment with these compounds did not result in nuclear uptake of the AhR. In contrast, treatment of BxPC3 and L3.6pL cells with these AhR ligands resulted in induction of CYP1A1 (by TCDD) and nuclear uptake of the AhR which was similar to that observed for Ah-responsive MDA-MB-468 breast and HepG2 liver cancer cell lines. Results of AhR and AhR nuclear translocator (Arnt) knockdown experiments in Panc1 and MiaPaCa2 cells demonstrate that omeprazole- and tranilast-mediated inhibition of invasion was AhR-dependent but Arnt-independent. These results demonstrate that in the most highly invasive sub-type of pancreatic cancer cells (QM-PDA), the selective AhR modulators omeprazole and tranilast inhibit invasion through a non-genomic AhR pathway.
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- 2015
19. [Massive upper gastrointestinal bleeding from multiple gastrointestinal stromal tumor in a neurofibromatosis patient]
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Woo Chul Chung and Sang Bae Kim
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Male ,medicine.medical_specialty ,Neurofibromatosis 1 ,business.industry ,Gastrointestinal Stromal Tumors ,General Medicine ,Middle Aged ,medicine.disease ,Gastroenterology ,Proto-Oncogene Proteins c-kit ,Jejunum ,Internal medicine ,Medicine ,Humans ,Upper gastrointestinal bleeding ,Endoscopy, Digestive System ,Stromal tumor ,Neurofibromatosis ,business ,Gastrointestinal Hemorrhage ,Radionuclide Imaging ,Tomography, X-Ray Computed - Published
- 2015
20. Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation
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Sung Sook Lee, Ji Hoon Kim, Ahmed Omar Kaseb, Jeong Eun Yoo, Snorri S. Thorgeirsson, Sung Soo Kim, Kwan Soo Byun, Xin Wei Wang, Bo Hwa Sohn, Young Nyun Park, Yun Yong Park, Sang Bae Kim, In Sun Chu, Koo Jeong Kang, Wan Bae Kim, Woojin Jeong, Jong Eun Yeon, Baek Hui Kim, Ju Seog Lee, Hyun-Sung Lee, Eun Sung Park, Jeonghoon Heo, and John M. Luk
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Adult ,Male ,STAT3 Transcription Factor ,Oncology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Multivariate analysis ,medicine.medical_treatment ,lcsh:Medicine ,Gastroenterology and Hepatology ,Liver transplantation ,Young Adult ,Diagnostic Medicine ,Risk Factors ,Surgical oncology ,Internal medicine ,Gastrointestinal Tumors ,Medicine and Health Sciences ,medicine ,Carcinoma ,Humans ,Aged ,Framingham Risk Score ,business.industry ,Liver Diseases ,Liver Neoplasms ,Hazard ratio ,lcsh:R ,food and beverages ,Cancers and Neoplasms ,Hepatocellular Carcinoma ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,digestive system diseases ,Confidence interval ,Surgery ,Hepatocellular carcinoma ,Multivariate Analysis ,Female ,Neoplasm Recurrence, Local ,business ,Research Article - Abstract
In this study, Lee and colleagues develop a genomic predictor that can identify patients at high risk for late recurrence of hepatocellular carcinoma (HCC) and provided new biomarkers for risk stratification., Background Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications. Methods and Findings Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3–3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (, Editors' Summary Background Primary liver cancer—a tumor that starts when a liver cell acquires genetic changes that allow it to grow uncontrollably—is the second-leading cause of cancer-related deaths worldwide, killing more than 600,000 people annually. If hepatocellular cancer (HCC; the most common type of liver cancer) is diagnosed in its early stages, it can be treated by surgically removing part of the liver (resection), by liver transplantation, or by local ablation, which uses an electric current to destroy the cancer cells. Unfortunately, the symptoms of HCC, which include weight loss, tiredness, and jaundice (yellowing of the skin and eyes), are vague and rarely appear until the cancer has spread throughout the liver. Consequently, HCC is rarely diagnosed before the cancer is advanced and untreatable, and has a poor prognosis (likely outcome)—fewer than 5% of patients survive for five or more years after diagnosis. The exact cause of HCC is unclear, but chronic liver (hepatic) injury and inflammation (caused, for example, by infection with hepatitis B virus [HBV] or by alcohol abuse) promote tumor development. Why Was This Study Done? Even when it is diagnosed early, HCC has a poor prognosis because it often recurs. Patients treated for HCC can experience two distinct types of tumor recurrence. Early recurrence, which usually happens within the first two years after surgery, arises from the spread of primary cancer cells into the surrounding liver that left behind during surgery. Late recurrence, which typically happens more than two years after surgery, involves the development of completely new tumors and seems to be the result of chronic liver damage. Because early and late recurrence have different clinical courses, it would be useful to be able to predict which patients are at high risk of which type of recurrence. Given that injury, inflammation, and regeneration seem to prime the liver for HCC development, might the gene expression patterns associated with these conditions serve as predictive markers for the identification of patients at risk of late recurrence of HCC? Here, the researchers develop a genomic predictor for the late recurrence of HCC by examining gene expression patterns in tissue samples from livers that were undergoing injury and regeneration. What Did the Researchers Do and Find? By comparing gene expression data obtained from liver biopsies taken before and after liver transplantation or resection and recorded in the US National Center for Biotechnology Information Gene Expression Omnibus database, the researchers identified 233 genes whose expression in liver differed before and after liver injury (the hepatic injury and regeneration, or HIR, signature). Statistical analyses indicate that the expression of the HIR signature in archived tissue samples was significantly associated with late recurrence of HCC in three independent groups of patients, but not with early recurrence (a significant association between two variables is one that is unlikely to have arisen by chance). By contrast, a tumor-derived 65-gene signature previously developed by the researchers was significantly associated with early recurrence but not with late recurrence. Notably, as few as four genes from the HIR signature were sufficient to construct a reliable predictor for late recurrence of HCC. Finally, the researchers report that many of the genes in the HIR signature encode proteins involved in inflammation and cell death, but that others encode proteins involved in cellular growth and proliferation such as STAT3, a protein with a well-known role in liver regeneration. What Do These Findings Mean? These findings identify a gene expression signature that was significantly associated with late recurrence of HCC in three independent groups of patients. Because most of these patients were infected with HBV, the ability of the HIR signature to predict late occurrence of HCC may be limited to HBV-related HCC and may not be generalizable to HCC related to other causes. Moreover, the predictive ability of the HIR signature needs to be tested in a prospective study in which samples are taken and analyzed at baseline and patients are followed to see whether their HCC recurs; the current retrospective study analyzed stored tissue samples. Importantly, however, the HIR signature associated with late recurrence and the 65-gene signature associated with early recurrence provide new insights into the biological differences between late and early recurrence of HCC at the molecular level. Knowing about these differences may lead to new treatments for HCC and may help clinicians choose the most appropriate treatments for their patients. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001770. The US National Cancer Institute provides information about all aspects of cancer, including detailed information for patients and professionals about primary liver cancer (in English and Spanish) The American Cancer Society also provides information about liver cancer (including information on support programs and services; available in several languages) The UK National Health Service Choices website provides information about primary liver cancer (including a video about coping with cancer) Cancer Research UK (a not-for-profit organization) also provides detailed information about primary liver cancer (including information about living with primary liver cancer) MD Anderson Cancer Center provides information about symptoms, diagnosis, treatment, and prevention of primary liver cancer MedlinePlus provides links to further resources about liver cancer (in English and Spanish)
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- 2014
21. Significant association of oncogene YAP1 with poor prognosis and cetuximab resistance in colorectal cancer patients
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Scott Kopetz, Keun Wook Lee, Sang Bae Kim, Yun Yong Park, Sang Cheul Oh, Bo Hwa Sohn, Sung Soo Kim, Ju Seog Lee, Hyun-Sung Lee, Hee Jin Jang, and Sung Sook Lee
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Oncology ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Cetuximab ,Antineoplastic Agents ,Disease ,Antibodies, Monoclonal, Humanized ,Disease-Free Survival ,Article ,Internal medicine ,Cell Line, Tumor ,medicine ,Humans ,Stage (cooking) ,Adaptor Proteins, Signal Transducing ,Hippo signaling pathway ,Oncogene ,business.industry ,Hazard ratio ,Cancer ,YAP-Signaling Proteins ,medicine.disease ,Phosphoproteins ,Prognosis ,Treatment Outcome ,Drug Resistance, Neoplasm ,Cancer research ,business ,Colorectal Neoplasms ,Transcriptome ,medicine.drug ,Transcription Factors - Abstract
Purpose: Activation of YAP1, a novel oncogene in the Hippo pathway, has been observed in many cancers, including colorectal cancer. We investigated whether activation of YAP1 is significantly associated with prognosis or treatment outcomes in colorectal cancer. Experimental Design: A gene expression signature reflecting YAP1 activation was identified in colorectal cancer cells, and patients with colorectal cancer were stratified into two groups according to this signature: activated YAP1 colorectal cancer (AYCC) or inactivated YAP1 colorectal cancer (IYCC). Stratified patients in five test cohorts were evaluated to determine the effect of the signature on colorectal cancer prognosis and response to cetuximab treatment. Results: The activated YAP1 signature was associated with poor prognosis for colorectal cancer in four independent patient cohorts with stage I–III disease (total n = 1,028). In a multivariate analysis, the impact of the YAP1 signature on disease-free survival was independent of other clinical variables [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.25–2.13; P < 0.001]. In patients with stage IV colorectal cancer and wild-type KRAS, IYCC patients had a better disease control rate and progression-free survival (PFS) after cetuximab monotherapy than did AYCC patients; however, in patients with KRAS mutations, PFS duration after cetuximab monotherapy was not different between IYCC and AYCC patients. In multivariate analysis, the effect of YAP1 activation on PFS was independent of KRAS mutation status and other clinical variables (HR, 1.82; 95% CI, 1.05–3.16; P = 0.03). Conclusions: Activation of YAP1 is highly associated with poor prognosis for colorectal cancer and may be useful in identifying patients with metastatic colorectal cancer resistant to cetuximab. Clin Cancer Res; 21(2); 357–64. ©2014 AACR.
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- 2014
22. Correction: Comparison of Prognostic Genomic Predictors in Colorectal Cancer
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Woojin Jeong, Ju Seog Lee, Sang Cheul Oh, Jae Yun Lim, Bo Hwa Sohn, Scott Kopetz, Sung Sook Lee, In-Sun Chu, Eun Sung Park, Sang Bae Kim, Sang Cheol Kim, Sung-Soo Kim, and Yun-Yong Park
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Oncology ,medicine.medical_specialty ,Multidisciplinary ,Colorectal cancer ,business.industry ,Science ,lcsh:R ,lcsh:Medicine ,Correction ,Medical research ,Bioinformatics ,medicine.disease ,Internal medicine ,medicine ,Medicine ,lcsh:Q ,lcsh:Science ,business - Abstract
Affiliation number 9 for the 11th and last authors is incorrect. The correct affiliation is: Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyunghee University, Seoul, Korea.
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- 2013
23. ATP11B mediates platinum resistance in ovarian cancer
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Sang Bae Kim, Justin Bottsford-Miller, Kshipra M. Gharpure, Lingegowda S. Mangala, Archana S. Nagaraja, Zahid H. Siddik, Chunhua Lu, Yu Kang, Robert R. Langley, Jeremy E. Coffin, Myrthala Moreno-Smith, William Bornman, Gabriel Lopez-Berestein, Paul S. Meltzer, Cristina Ivan, Anil K. Sood, Margaret S. Halleck, Behrouz Zand, Mary J.C. Hendrix, Pablo E. Vivas-Mejia, Menashe Bar-Eli, Hua Wang, Rosemarie Schmandt, Rajesha Rupaimoole, Tamas A. Gonda, Jyotsnabaran Halder, Nicholas B. Jennings, Cristian Rodriguez-Aguayo, Guillermo N. Armaiz, and Ju Seog Lee
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Expression of Concern ,Oncology ,Pathology ,medicine.medical_specialty ,DNA damage ,Golgi Apparatus ,Antineoplastic Agents ,R-SNARE Proteins ,Mice ,Cell Line, Tumor ,Clinical investigation ,Platinum resistance ,Internal medicine ,Animals ,Humans ,Gene silencing ,Medicine ,Gene Silencing ,RNA, Small Interfering ,Fluorescent Dyes ,Adenosine Triphosphatases ,Ovarian Neoplasms ,Cisplatin ,biology ,Qa-SNARE Proteins ,Membrane transport protein ,business.industry ,Carcinoma ,Cell Membrane ,Membrane Transport Proteins ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Vesicular transport protein ,Membrane protein ,Drug Resistance, Neoplasm ,biology.protein ,Cancer research ,ATP-Binding Cassette Transporters ,Female ,business ,Ovarian cancer ,Corrigendum ,Research Article ,medicine.drug - Abstract
Platinum compounds display clinical activity against a wide variety of solid tumors; however, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. We found that ATP11B expression was correlated with higher tumor grade in human ovarian cancer samples and with cisplatin resistance in human ovarian cancer cell lines. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-targeted siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux kinetics indicated that ATP11B enhances the export of cisplatin from cells. The colocalization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins, such as syntaxin-6 (STX6) and vesicular-associated membrane protein 4 (VAMP4), strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, inhibition of ATP11B expression could serve as a therapeutic strategy to overcome cisplatin resistance.
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- 2013
24. The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis
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Johannes von Burstin, Sang Bae Kim, Anil K. Rustgi, Kaori Ihida-Stansbury, Maximilian Reichert, S. Heeg, Ju Seog Lee, Shigetsugu Takano, Günter Schneider, Andrew D. Rhim, Ben Z. Stanger, and Christopher Hahn
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Pancreatic Intraepithelial Neoplasia ,Biology ,medicine.disease_cause ,Mice ,Pancreatic cancer ,Metaplasia ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Protein Isoforms ,Regeneration ,Promoter Regions, Genetic ,Pancreas ,Cells, Cultured ,Regulation of gene expression ,Homeodomain Proteins ,Regeneration (biology) ,Gene Expression Profiling ,SOX9 Transcription Factor ,medicine.disease ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Gene Expression Regulation ,Cancer research ,Pancreatitis ,medicine.symptom ,Carcinogenesis ,Developmental Biology ,Protein Binding ,Research Paper - Abstract
Pancreatic exocrine cell plasticity can be observed during development, pancreatitis with subsequent regeneration, and also transformation. For example, acinar–ductal metaplasia (ADM) occurs during acute pancreatitis and might be viewed as a prelude to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) development. To elucidate regulatory processes that overlap ductal development, ADM, and the progression of normal cells to PanIN lesions, we undertook a systematic approach to identify the Prrx1 paired homeodomain Prrx1 transcriptional factor as a highly regulated gene in these processes. Prrx1 annotates a subset of pancreatic ductal epithelial cells in Prrx1creERT2-IRES-GFP mice. Furthermore, sorted Prrx1+ cells have the capacity to self-renew and expand during chronic pancreatitis. The two isoforms, Prrx1a and Prrx1b, regulate migration and invasion, respectively, in pancreatic cancer cells. In addition, Prrx1b is enriched in circulating pancreatic cells (Pdx1cre;LSL-KrasG12D/+;p53fl/+;R26YFP). Intriguingly, the Prrx1b isoform, which is also induced in ADM, binds the Sox9 promoter and positively regulates Sox9 expression. This suggests a new hierarchical scheme whereby a Prrx1–Sox9 axis may influence the emergence of acinar–ductal metaplasia and regeneration. Furthermore, our data provide a possible explanation of why pancreatic cancer is skewed toward a ductal fate.
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- 2013
25. Development and Validation of a Prognostic Gene-Expression Signature for Lung Adenocarcinoma
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Woojin Jeong, Bo Hwa Sohn, Gordon B. Mills, Ju Seog Lee, Yun Yong Park, Lauren Averett Byers, Eun Sung Park, Sang Bae Kim, Sang Cheol Kim, and In Sun Chu
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Oncology ,Male ,Lung Neoplasms ,Cancer Treatment ,lcsh:Medicine ,Gene Expression ,Bioinformatics ,Biochemistry ,Lung and Intrathoracic Tumors ,Cohort Studies ,Small Cell Lung Cancer ,Basic Cancer Research ,Cluster Analysis ,lcsh:Science ,Aged, 80 and over ,Multidisciplinary ,Adenocarcinoma of the Lung ,Hazard ratio ,Genomics ,Middle Aged ,Prognosis ,Gene Expression Regulation, Neoplastic ,Chemotherapy, Adjuvant ,Adenocarcinoma ,Medicine ,Female ,Research Article ,Subset Analysis ,Adult ,medicine.medical_specialty ,Adenocarcinoma of Lung ,Internal medicine ,DNA-binding proteins ,medicine ,Adenocarcinoma of the lung ,Genetics ,Humans ,Lung cancer ,Biology ,Survival analysis ,Aged ,Proportional Hazards Models ,Models, Genetic ,Proportional hazards model ,business.industry ,lcsh:R ,Proteins ,Cancers and Neoplasms ,Reproducibility of Results ,Gene signature ,Chemotherapy and Drug Treatment ,medicine.disease ,Survival Analysis ,Multivariate Analysis ,lcsh:Q ,business ,Genome Expression Analysis ,Transcriptome ,Genes, Neoplasm - Abstract
Although several prognostic signatures have been developed in lung cancer, their application in clinical practice has been limited because they have not been validated in multiple independent data sets. Moreover, the lack of common genes between the signatures makes it difficult to know what biological process may be reflected or measured by the signature. By using classical data exploration approach with gene expression data from patients with lung adenocarcinoma (n = 186), we uncovered two distinct subgroups of lung adenocarcinoma and identified prognostic 193-gene gene expression signature associated with two subgroups. The signature was validated in 4 independent lung adenocarcinoma cohorts, including 556 patients. In multivariate analysis, the signature was an independent predictor of overall survival (hazard ratio, 2.4; 95% confidence interval, 1.2 to 4.8; p = 0.01). An integrated analysis of the signature revealed that E2F1 plays key roles in regulating genes in the signature. Subset analysis demonstrated that the gene signature could identify high-risk patients in early stage (stage I disease), and patients who would have benefit of adjuvant chemotherapy. Thus, our study provided evidence for molecular basis of clinically relevant two distinct two subtypes of lung adenocarcinoma.
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- 2012
26. FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair
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Kyounghyun Kim, Sang Bae Kim, Sung Yun Jung, Anil K. Sood, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo, Guang Peng, Shiaw Yih Lin, Se Ran Lee, Sun Hee Leem, Yun Yong Park, Ju Seog Lee, and Nicholas B. Jennings
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Cancer Research ,DNA damage ,DNA repair ,Cancer ,Original Manuscript ,General Medicine ,Biology ,medicine.disease ,Breast cancer ,Cancer research ,medicine ,FOXM1 ,polycyclic compounds ,Gene silencing ,Doxorubicin ,Transcription factor ,medicine.drug - Abstract
Transcription factors are direct effectors of altered signaling pathways in cancer and frequently determine clinical outcomes in cancer patients. To uncover new transcription factors that would determine clinical outcomes in breast cancer, we systematically analyzed gene expression data from breast cancer patients. Our results revealed that Forkhead box protein M1 (FOXM1) is the top-ranked survival-associated transcription factor in patients with triple-negative breast cancer. Surprisingly, silencing FOXM1 expression led breast cancer cells to become more sensitive to doxorubicin (Dox). We found that FOXM1-dependent resistance to Dox is mediated by regulating DNA repair genes. We further demonstrated that NFκB1 interacts with FOXM1 in the presence of Dox to protect breast cancer cells from DNA damage. Finally, silencing FOXM1 expression in breast cancer cells in a mouse xenograft model significantly sensitized the cells to Dox. Our systematic approaches identified an unexpected role of FOXM1 in Dox resistance by regulating DNA repair genes, and our findings provide mechanistic insights into how FOXM1 mediates resistance to Dox and evidence that FOXM1 may be a promising therapeutic target for sensitizing breast cancer cells to Dox.
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- 2012
27. Clinical Outcomes of the Marginal Ulcer Bleeding after Gastrectomy: As Compared to the Peptic Ulcer Bleeding with Nonoperated Stomach
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Hyung Min Chin, Woo Chul Chung, Eun Jung Jeon, Kang-Moon Lee, Chang Nyol Paik, Yang Woon Lee, Kyong-Hwa Jun, Sang Bae Kim, and You Suk Oh
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medicine.medical_specialty ,Article Subject ,medicine.medical_treatment ,Gastroenterology ,Internal medicine ,medicine ,Helicobacter ,lcsh:RC799-869 ,Hepatology ,biology ,business.industry ,Stomach ,Mortality rate ,biology.organism_classification ,medicine.disease ,Marginal Ulcer ,Surgery ,medicine.anatomical_structure ,Hemostasis ,lcsh:Diseases of the digestive system. Gastroenterology ,Gastrectomy ,Upper gastrointestinal bleeding ,business ,Complication ,Research Article - Abstract
Background. Marginal ulcer is a well-known complication after gastrectomy. Its bleeding can be severe, but the severity has rarely been reported. We aim to evaluate the clinical outcomes of marginal ulcer bleeding (MUB) as compared to peptic ulcer bleeding (PUB) with nonoperated stomach.Methods. A consecutive series of patients who had nonvariceal upper gastrointestinal bleeding and admitted to the hospital between 2005 and 2011 were retrospectively analyzed. A total of 530 patients were enrolled in this study, and we compared the clinical characteristics between 70 patients with MUB and 460 patients with PUB.Results. Patients with MUB were older (mean age:62.86±10.59years versus53.33±16.68years,P=0.01). The initial hemoglobin was lower (8.16±3.05 g/dL versus9.38±2.49 g/dL,P=0.01), and the duration of admission was longer in MUB (7.14±4.10days versus5.90±2.97days,P=0.03). After initial hemostasis, the rebleeding rate during admission was higher (16.2% versus 6.5%,P=0.01) in MUB. However, the mortality rate did not differ statistically between MUB and PUB groups.Helicobacter pylori-positive rate with MUB was lower than that of PUB (19.4% versus 54.4%,P=0.01).Conclusions. Clinically, MUB after gastrectomy is more severe than PUB with nonoperated stomach. Infection withH. pylorimight not appear to play an important role in MUB after gastrectomy.
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- 2012
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28. First generation prognostic gene signatures for breast cancer predict both survival and chemotherapy sensitivity and identify overlapping patient populations
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Rebekah Hubbard, Elliana Young, Takayuki Iwamoto, Gabriel N. Hortobagyi, Junji Matsuoka, Lajos Pusztai, Ju Seog Lee, Sang Bae Kim, Giampaolo Bianchini, and W. Fraser Symmans
- Subjects
Oncology ,Adult ,Risk ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Breast Neoplasms ,Bioinformatics ,Breast cancer ,Internal medicine ,Biomarkers, Tumor ,Medicine ,Humans ,Survival analysis ,Aged ,Neoplasm Staging ,Predictive marker ,Receiver operating characteristic ,business.industry ,Gene Expression Profiling ,Univariate ,Odds ratio ,Middle Aged ,medicine.disease ,Prognosis ,Gene Expression Regulation, Neoplastic ,Treatment Outcome ,Cohort ,Female ,business - Abstract
The aims of this study were to compare the performance of six different genomic prognostic markers to predict long-term survival and chemotherapy response on the same patient cohort and assess if clinicopathological variables carry independent prognostic and predictive values. We examined seven clinical variables and six previously described prognostic signatures on 228 tumors from patients who received homogeneous preoperative chemotherapy and had long-term follow-up information for survival. We used the area under the receiver operator characteristic curve (AUC) to compare predictors and also performed univariate and multivariate analyses including the genomic and clinical variables and plotted Kaplan-Meir survival curves. All genomic prognostic markers had statistically similar AUCs and sensitivity to predict 5-year progression-free survival (PFS, sensitivities ranged from 0.591 to 0.773, and AUCs: 0.599-0.673), overall survival (OS, sensitivities: 0.590-0.769, AUCs: 0.596-0.684) and pathologic complete response (pCR, sensitivities: 0.596-0.851, AUCs: 0.614-0.805). In multivariate analysis, the genomic markers were not independent from one another; however, estrogen receptor (Odds Ratio [OR] 7.63, P < 0.001) and HER2 status (OR: 0.37, P = 0.021) showed significant independent predictive values for pCR. Nodal status remained an independent prognostic, but not predictive, variable (OR for PFS: 2.77, P = 0.021, OR for OS: 3.62, P = 0.01). There was moderate to good agreement between different prediction results in pair-wise comparisons. First-generation prognostic-gene signatures predict both chemotherapy response and long-term survival. When multiple predictors are applied to the same case discordant risk prediction frequently occurs.
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- 2011
29. Gene expression signature–based prognostic risk score in gastric cancer
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Young Nyun Park, Soo Mi Kim, Jae Yong Cho, Ju Seog Lee, Se Lyun Yoon, Sang Bae Kim, Hoguen Kim, In Sun Chu, Jaffer A. Ajani, Yun Yong Park, Jae Yun Lim, Jae Ho Cheong, Waun Ki Hong, Sung Hoon Noh, Soon Won Hong, and Eun Sung Park
- Subjects
Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Gastrointestinal Stromal Tumors ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Adenocarcinoma ,Bioinformatics ,Article ,Disease-Free Survival ,Stomach Neoplasms ,Internal medicine ,Biomarkers, Tumor ,Odds Ratio ,Medicine ,Humans ,Aged ,Oligonucleotide Array Sequence Analysis ,Proportional Hazards Models ,Aged, 80 and over ,Framingham Risk Score ,business.industry ,Proportional hazards model ,Gene Expression Profiling ,Cancer ,Odds ratio ,Middle Aged ,medicine.disease ,Prognosis ,ROC Curve ,Cohort ,Multivariate Analysis ,Biomarker (medicine) ,Gastrectomy ,Female ,Neoplasm Recurrence, Local ,business - Abstract
Purpose: Despite continual efforts to develop a prognostic model of gastric cancer by using clinical and pathologic parameters, a clinical test that can discriminate patients with good outcomes from those with poor outcomes after gastric cancer surgery has not been established. We aim to develop practical biomarker-based risk score that can predict relapse of gastric cancer after surgical treatment. Experimental Design: Microarray technologies were used to generate and analyze gene expression profiling data from 65 gastric cancer patients to identify biomarker genes associated with relapse. The association of expression patterns of identified genes with relapse and overall survival was validated in independent gastric cancer patients. Results: We uncovered two subgroups of gastric cancer that were strongly associated with the prognosis. For the easy translation of our findings into practice, we developed a scoring system based on the expression of six genes that predicted the likelihood of relapse after curative resection. In multivariate analysis, the risk score was an independent predictor of relapse in a cohort of 96 patients. We were able to validate the robustness of the six-gene signature in an additional independent cohort. Conclusions: The risk score derived from the six-gene set successfully prognosticated the relapse of gastric cancer patients after gastrectomy. Clin Cancer Res; 17(7); 1850–7. ©2011 AACR.
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- 2011
30. Expression signature of E2F1 and its associated genes predict superficial to invasive progression of bladder tumors
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Wun-Jae Kim, Eun Sung Park, In Sun Chu, Sang Bae Kim, Yong-June Kim, Sang-Yeop Lee, Sun Hee Leem, Sang Cheol Kim, Ju Seog Lee, and Seon-Kyu Kim
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Expression Signature ,Risk Assessment ,Cohort Studies ,Young Adult ,Text mining ,E2F2 Transcription Factor ,Predictive Value of Tests ,Internal medicine ,Gene expression ,medicine ,E2F1 ,Humans ,Neoplasm Invasiveness ,RNA, Neoplasm ,Gene ,Aged ,Neoplasm Staging ,Proportional Hazards Models ,Retrospective Studies ,Aged, 80 and over ,Analysis of Variance ,Carcinoma, Transitional Cell ,Bladder cancer ,business.industry ,Gene Expression Profiling ,Biopsy, Needle ,Cystoscopy ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Survival Analysis ,Gene Expression Regulation, Neoplastic ,Urinary Bladder Neoplasms ,Cohort ,Multivariate Analysis ,Disease Progression ,Female ,business ,After treatment - Abstract
Purpose In approximately 20% of patients with superficial bladder tumors, the tumors progress to invasive tumors after treatment. Current methods of predicting the clinical behavior of these tumors prospectively are unreliable. We aim to identify a molecular signature that can reliably identify patients with high-risk superficial tumors that are likely to progress to invasive tumors. Patients and Methods Gene expression data were collected from tumor specimens from 165 patients with bladder cancer. Various statistical methods, including leave-one-out cross-validation methods, were applied to identify a gene expression signature that could predict the likelihood of progression to invasive tumors and to test the robustness of the expression signature in an independent cohort. The robustness of the gene expression signature was validated in an independent (n = 353) cohort. Results Supervised analysis of gene expression data revealed a gene expression signature that is strongly associated with invasive bladder tumors. A molecular classifier based on this gene expression signature correctly predicted the likelihood of progression of superficial tumor to invasive tumor. Conclusion We present a molecular signature that can predict, at diagnosis, the likelihood of bladder cancer progression and, possibly, lead to improvements in patient therapy.
- Published
- 2010
31. Identification of molecular markers for the oncogenic differentiation of hepatocellular carcinoma
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Baik Hwan Cho, Sang Bae Kim, Gyung Ran Yu, In Sun Chu, Young Il Yeom, Seong Hun Kim, Dong Yuan Xu, Xiang Dan Cui, Hee Chul Yu, Sangsoo Kim, Dae Ghon Kim, and Seon Hwa Park
- Subjects
Carcinoma, Hepatocellular ,Tumor suppressor gene ,Microarray ,Clinical Biochemistry ,Biology ,Biochemistry ,Subclass ,Gene expression ,Carcinoma ,medicine ,Biomarkers, Tumor ,Humans ,Genes, Tumor Suppressor ,Molecular Biology ,Gene ,Annexin A2 ,Oligonucleotide Array Sequence Analysis ,Gene Expression Profiling ,Liver Neoplasms ,Oncogenes ,medicine.disease ,Molecular biology ,digestive system diseases ,Gene expression profiling ,Hepatocellular carcinoma ,Multigene Family ,Cancer research ,Molecular Medicine ,Molecular Chaperones - Abstract
The aim of this study was to identify molecular markers associated with oncogenic differentiation in hepatocellular carcinoma (HCC). Using an unsupervised clustering method with a cDNA microarray, HCC (T) gene expression profiles and corresponding non-tumor tissues (NT) from 40 patients were analyzed. Of total 217 genes, 72 were expressed preferentially in HCC tissues. Among 186 differentially regulated genes, there were molecular chaperone and tumor suppressor gene clusters in the Edmondson grades I and II (GI/II) subclass compared with the liver cirrhosis (LC) subclass. The Edmondson grades III and IV (GIII/IV) subclass with a poor survival (P = 0.0133) contained 122 differentially regulated genes with a cluster containing various metastasis- and invasion-related genes compared with the GI/II subclass. Immunohistochemical analysis revealed that ANXA2, one of the 72 genes preferentially expressed in HCC, was over-expressed in the sinusoidal endothelium and in malignant hepatocytes in HCC. The genes identified in the HCC subclasses will be useful molecular markers for the genesis and progression of HCC. In addition, ANXA2 might be a novel marker for tumor angiogenesis in HCC.
- Published
- 2007
32. Abstract 892: Vitamin D deficiency regulates TLR7 to promote hepatocellular cancer in TGF-β/Smad3 heterozygous mice
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Lior H. Katz, Nina M. Muñoz, Jian Chen, Hidekazu Tsukamoto, Ji-Hyun Shin, Aiwu R. He, Keigo Machida, Asif Rashid, Ju Seog Lee, Vivek Shukla, Lopa Mishra, Lynt B. Johnson, Sang Bae Kim, Franklin Herlong, Kirti Shetty, and Andrea Cortes
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Cancer Research ,medicine.medical_specialty ,Cirrhosis ,business.industry ,Wnt signaling pathway ,medicine.disease ,vitamin D deficiency ,STAT5A ,Real-time polymerase chain reaction ,Endocrinology ,Oncology ,Hepatocellular carcinoma ,Internal medicine ,medicine ,Vitamin D and neurology ,Immunohistochemistry ,business - Abstract
Hepatocellular carcinoma (HCC) is the fifth most common tumor and the third leading cause of cancer-related deaths. Loss of TGF-β signaling has been associated with development of HCC. Cancer preventive effects of Vitamin D (VD) have been implicated in multiple cancers, however a clear role for Vitamin D in specific high risk populations remains undefined for HCC. Therefore, we examined for a potential chemopreventive role of VD in HCC in the context of TGF-β inactivation. Methods: (1) We screened for somatic mutation of the TGF-β pathway and VD related genes in 202 HCCs from The Cancer Genome Atlas (TCGA). (2) Wild type, Sptbn1+/- and Smad3+/- mice were fed with low VD (200 IU VD/kg) or high VD diet (10,000 IU VD/kg) for 9 weeks. Liver tissues were subjected to microarray analyses and further evaluation by quantitative PCR. (3) Wild type, Sptbn1+/- and Smad3+/- mice were injected Diethylnitrosamine (DEN) and at 8 month, 26 mice receiving low VD (200 IU VD/kg) and 26 mice receiving high VD (10,000 IU VD/kg) chow. HCC development was assessed at 4 months after VD treatment. (4) Reverse Phase Protein Array (RPPA) was performed to analyze expression profiles of 164 proteins of mouse liver tumors. (5) Liver samples from patients with HCV cirrhosis receiving VD supplements were examined to evaluate expression of TGF-β, Wnt and VD pathway molecules by immunohistochemistry. Results: (1) We observed a high rate of somatic mutation in TGF-β and VD pathway related genes in the TCGA genomic analysis. (2) None of the VD treated mice developed HCC but high VD treatment increased TLR7 mRNA expression about 3-fold in liver from Smad3+/- mice compared with livers from WT mice. (3) Smad3+/- mice with low VD showed 3-fold larger HCC formation, compared to the high VD group (Smad3+/-) that did not develop significant tumors. However, correction of VD in the Chow after 10 months did not reverse HCC formation. (4) RPPA data revealed that the tumor suppressor protein PDCD4 was reduced in Smad3+/- mice with low VD treatment. However, oncoproteins such as β-catenin, Stat5A and Bcl2-XL were induced in the same sample. (5) Expression of β2SP and TβRII were higher in HCV cirrhosis patients receiving VD supplementation compared to non-treated group. Conclusions: Loss of TGF-β signaling pathway developed HCC and VD deficiency promotes tumor growth in the context of Smad3 disruption potentially through regulation of TLR7 expression. However, after 10 months restoring VD does not have any significant effect on altering tumors. Therefore VD could be a potential candidate for prevention in early identified HCC high risk individuals who has inactivation of TGF-β/Smad3 signaling. Citation Format: Ji-hyun Shin, Lior H. Katz, Nina M. Munoz, Andrea Cortes, Vivek Shukla, Sang-Bae Kim, Franklin Herlong, Keigo Machida, Hidekazu Tsukamoto, Kirti Shetty, Aiwu R. He, Lynt B. Johnson, Asif Rashid, Jian Chen, Ju-Seog Lee, Lopa Mishra. Vitamin D deficiency regulates TLR7 to promote hepatocellular cancer in TGF-β/Smad3 heterozygous mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 892. doi:10.1158/1538-7445.AM2015-892
- Published
- 2015
33. Sa1954 Vitamin D Deficiency Promotes Hepatocellular Cancer via Regulating TLR7 in the Context of Loss of TGF-β/Smad3
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Keigo Machida, Vivek Shukla, Kirti Shetty, Aiwu R. He, Lior H. Katz, Lynt B. Johnson, Randa El-Zein, Hidekazu Tsukamoto, Asif Rashid, Sang Bae Kim, Ju Seog Lee, Franklin Herlong, Nina M. Muñoz, Jian Chen, Andrea Cortes, Ji-Hyun Shin, and Lopa Mishra
- Subjects
Hepatocellular cancer ,Hepatology ,business.industry ,Gastroenterology ,Cancer research ,medicine ,Context (language use) ,TLR7 ,medicine.disease ,business ,vitamin D deficiency ,Transforming growth factor - Published
- 2015
34. Abstract 4734: Activation of yap1 is significantly associated with poor prognosis and cetuximab resistance in colorectal cancer patients
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Keun-Wook Lee, Sang Bae Kim, Ju Seog Lee, Sung Sook Lee, Yun-Yong Park, Bo Hwa Sohn, and Hyun-Sung Lee
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Oncology ,Cancer Research ,medicine.medical_specialty ,Cetuximab ,business.industry ,Colorectal cancer ,Hazard ratio ,Cancer ,medicine.disease ,medicine.disease_cause ,digestive system diseases ,Internal medicine ,Immunology ,medicine ,Clinical significance ,KRAS ,Stage (cooking) ,business ,neoplasms ,Survival rate ,medicine.drug - Abstract
Purpose: To investigate the clinical significance of activation of YAP1, a newly identified oncogene in colorectal cancer (CRC). Patients and Methods: A gene expression signature reflecting YAP1 activation was identified in CRC cells, and CRC patients were stratified into two groups according to this signature: activated YAP1 CRC (AYCC) or inactivated YAP1 CRC (IYCC). Stratified patients in six test cohorts were evaluated to determine the effect of the signature on CRC prognosis and response to treatment with cetuximab. Results: The activated YAP1 signature was associated with poor prognosis for CRC in four independent patient cohorts with stage I-III disease (total n = 1,028). In a multivariate analysis, the impact of the YAP1 signature on the disease-free survival rate was independent of other clinical variables [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.25-2.13; P < .001]. In patients with stage IV CRC, AYCC patients had a poorer disease control rate and progression-free survival duration after cetuximab-based monotherapy than did IYCC patients (HR, 1.82; 95% CI, 1.05-3.16; P = .03). In multivariate analysis, the effect of YAP1 activation on PFS was independent of KRAS mutation status and cetuximab-based therapy was effective only in IYCC patients without KRAS mutations. Conclusion: Activation of YAP1 is highly associated with poor prognosis for CRC and may be useful in identifying patients with CRC resistant to treatment with cetuximab. Citation Format: Keun-Wook Lee, Sung Sook Lee, Sang-Bae Kim, Yun-Yong Park, Bo Hwa Sohn, Hyun-Sung Lee, Ju-Seog Lee. Activation of yap1 is significantly associated with poor prognosis and cetuximab resistance in colorectal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4734. doi:10.1158/1538-7445.AM2014-4734
- Published
- 2014
35. Abstract 248: Vitamin D deficiency promotes hepatocellular carcinoma tumor growth in TGF-β impaired mice by Smad3 heterozygous deletion
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Keigo Machida, K. Shetty, Ju Seog Lee, Asif Rashid, Nina M. Muñoz, Lynt B. Johnson, Sang Bae Kim, Lior H. Katz, Lopa Mishra, Hidekazu Tsukamoto, and Aiwu R. He
- Subjects
Cancer Research ,medicine.medical_specialty ,Tumor suppressor gene ,business.industry ,Cancer ,Context (language use) ,PDGFRB ,medicine.disease ,vitamin D deficiency ,Endocrinology ,Oncology ,Hepatocellular carcinoma ,Internal medicine ,Vitamin D and neurology ,medicine ,business ,Transforming growth factor - Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Vitamin D (VD) has been implicated in the prevention of multiple cancers, some of which are characterized by inactivation of TGF-β signaling. Recently, inactivation of TGF-β signaling has been associated with development of HCC. We examined the potential role of VD in HCC chemoprevention in the context of TGF-β inactivation in a mouse model. Methods: Wild type, Sptbn1+/- and Smad3+/- male mice were treated with 50 mg/kg of the chemical carcinogen diethylnitrosamine (DEN) via i.p. injection at 14 days of age. At 8 months, the animals were changed from regular chow (2,200 IU/kg VD) to one of two diets: lower than normal VD (200 IU/kg) or high VD (10,000 IU/kg). At one year of age, the livers were harvested for tissue analysis. Several metrics were assessed including expression levels of 164 proteins from liver tumors by Reverse Phase Protein Array (RPPA). Results: Twenty three mice were treated with lower than normal dose VD while 26 received high dose VD. We did not find significant differences in blood calcium levels in animals on either diet. As expected, high VD intervention after 8 months of DEN injection did not affect the total number of tumors the mice developed; however, the lower than normal VD regimen promoted tumor growth in the context of Smad3 disruption (liver-to-body weight ratio 18.37% in Smad3+/- mice treated with low dose VD vs. 6.25% in Smad3+/- animals treated with high dose, p=0.028). Furthermore, RPPA data revealed that the lower than normal VD intake in DEN-treated Smad3 heterozygous null mice results in repression of tumor suppressing genes such as PDCD4 and concomitant up-regulation of tumor promoting genes like Stat5A, Bcl2-XL, PDGFRB and PEA15. Conclusions: Remarkably, lower than normal VD in the context of Smad3 disruption promotes tumor growth possibly through repression of tumor suppressing genes such as PDCD4 and up-regulation of oncogenes like Stat5A, Bcl2-XL, PDGFRB and PEA15. These results suggest that VD treatment strategies could potentially be significant for chemoprevention and treatment of HCC in the context of inactivation of TGF-β signaling in patient populations with underlying deficiency of VD. Citation Format: Nina M. Muñoz, Lior H. Katz, Keigo Machida, Hidekazu Tsukamoto, Kirty Shetty, Aiwu R. He, Lynt B. Johnson, Asif Rashid, Sang Bae Kim, Ju-Seog Lee, Lopa Mishra. Vitamin D deficiency promotes hepatocellular carcinoma tumor growth in TGF-β impaired mice by Smad3 heterozygous deletion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 248. doi:10.1158/1538-7445.AM2014-248
- Published
- 2014
36. Mo1643 Diets With Subnormal Supplementation of Vitamin D Regimen Promote Hepatocellular Carcinoma Tumor Growth in TGF-β Impaired Mice With SMAD3 Heterozygous Deletion
- Author
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Lynt B. Johnson, Ju Seog Lee, Lopa Mishra, Lior H. Katz, Hidekazu Tsukamoto, Asif Rashid, Sang Bae Kim, Nina M. Muñoz, Keigo Machida, Kirti Shetty, and Aiwu R. He
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Gastroenterology ,medicine.disease ,Regimen ,Endocrinology ,Hepatocellular carcinoma ,Internal medicine ,Cancer research ,medicine ,Vitamin D and neurology ,Tumor growth ,business ,Transforming growth factor - Published
- 2014
37. Comparison of Prognostic Genomic Predictors in Colorectal Cancer
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Sang Cheul Oh, Sang Bae Kim, Sung Sook Lee, Sung Soo Kim, Bo Hwa Sohn, Scott Kopetz, Sang Cheol Kim, Jae Yun Lim, Woojin Jeong, In Sun Chu, Ju Seog Lee, Eun Sung Park, and Yun Yong Park
- Subjects
Male ,Research design ,Oncology ,Epidemiology ,Colorectal cancer ,Cancer Treatment ,Gene Expression ,Kaplan-Meier Estimate ,Bioinformatics ,Gastrointestinal Cancers ,Aged, 80 and over ,Multidisciplinary ,Genomics ,Middle Aged ,Neoplasm Proteins ,Research Design ,Predictive value of tests ,Medicine ,Female ,Colorectal Neoplasms ,Cancer Epidemiology ,Research Article ,Adult ,Genetic Markers ,medicine.medical_specialty ,Poor prognosis ,Disease free survival ,Science ,Concordance ,Gastroenterology and Hepatology ,Disease-Free Survival ,Rectal Cancer ,Predictive Value of Tests ,Internal medicine ,Gastrointestinal Tumors ,medicine ,Carcinoma ,Humans ,Biology ,Aged ,Comparative genomics ,business.industry ,Gene Expression Profiling ,Cancers and Neoplasms ,Chemotherapy and Drug Treatment ,medicine.disease ,Biomarker Epidemiology ,Genome Expression Analysis ,business - Abstract
BackgroundAlthough several prognostic genomic predictors have been identified from independent studies, it remains unclear whether these predictors are actually concordant with respect to their predictions for individual patients and which predictor performs best. We compared five prognostic genomic predictors, the V7RHS, the ColoGuideEx, the Meta163, the OncoDX, and the MDA114, in terms of predicting disease-free survival in two independent cohorts of patients with colorectal cancer.Study designUsing original classification algorithms, we tested the predictions of five genomic predictors for disease-free survival in two cohorts of patients with colorectal cancer (n = 229 and n = 168) and evaluated concordance of predictors in predicting outcomes for individual patients.ResultsWe found that only two predictors, OncoDX and MDA114, demonstrated robust performance in identifying patients with poor prognosis in 2 independent cohorts. These two predictors also had modest but significant concordance of predicted outcome (r>0.3, PConclusionsFurther validation of developed genomic predictors is necessary. Despite the limited number of genes shared by OncoDX and MDA114, individual-patient outcomes predicted by these two predictors were significantly concordant.
- Published
- 2013
38. Abstract 5398: TARDBP regulates glycolysis in hepatocellular carcinoma by regulating PFKP through miR-520
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Sang Bae Kim, Yun-Yong Park, Jiyong Liang, Bo-Hwa Sohn, Gordon B. Mills, Hee Dong Han, Yiling Lu, Anil K. Sood, and Ju Seog Lee
- Subjects
Cancer Research ,Cancer ,Biology ,Bioinformatics ,medicine.disease ,TARDBP ,Metabolic pathway ,Oncology ,Cancer cell ,PFKP ,Cancer research ,medicine ,Gene silencing ,Glycolysis ,Phosphofructokinase - Abstract
Metabolic changes are common features of many cancer cells and are frequently associated with the clinical outcome of patients with various cancers including hepatocellular carcinoma (HCC). Thus, aberrant metabolic pathways in cancer cells are attractive targets for cancer therapy. However, our understanding of cancer-specific regulatory mechanisms of cell metabolism is still very limited. We found that Tat activating regulatory DNA-binding protein (TARDBP) is a novel regulator of glycolysis in HCC cells. TARDBP regulates expression of the platelet isoform of phosphofructokinase (PFKP), the rate-limiting enzyme of glycolysis that catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Silencing of TARDBP expression in multiple HCC cell lines leads to impaired glucose metabolism and inhibition of in vitro and in vivo growth of HCC cells. Notably, the miR-520 family is an intermediate regulator of TARDBP-mediated regulation of glycolysis. Mechanistically, TARDBP suppressed expression of the miR-520 family, which in turn inhibited expression of PFKP. We further showed that expression of PFKP is significantly associated with the overall survival of patients with HCC. Our study provides new mechanistic insights into the regulation of glycolysis in HCC cells and reveals TARDBP as a potential therapeutic target for HCC. Citation Format: Yun-Yong Park, Sang Bae Kim, Hee Dong Han, Bo-Hwa Sohn, Jiyong Liang, Yiling Lu, Gordon Mills, Anil Sood, Ju-Seog Lee. TARDBP regulates glycolysis in hepatocellular carcinoma by regulating PFKP through miR-520. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5398. doi:10.1158/1538-7445.AM2013-5398
- Published
- 2013
39. Abstract 2962: FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair
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Anil K. Sood, Gabriel Lopez-Berestein, Yun-Yong Park, Sang Bae Kim, Cristian Rodriguez-Aguayo, Sung Yun Jung, Guang Peng, Shiaw-Yih Lin, Sun-Hee Leem, Se-Ra Lee, Kyounghyun Kim, and Ju Seog Lee
- Subjects
Cancer Research ,DNA repair ,business.industry ,DNA damage ,Cancer ,medicine.disease ,Breast cancer ,Oncology ,medicine ,Cancer research ,FOXM1 ,Gene silencing ,Doxorubicin ,business ,Transcription factor ,medicine.drug - Abstract
Transcription factors (TFs) are direct effectors of altered signaling pathways in cancer. To uncover new TFs that would determine clinical outcomes in breast cancer patients, we systematically analyzed gene expression data from breast cancer patients. Our results revealed that forkhead box protein M1 (FOXM1) is the top-ranked survival-associated TF with triple-negative breast cancer. Surprisingly, silencing FOXM1 expression led breast cancer cells to become more sensitive to doxorubicin (Dox). We found that FOXM1-dependent resistance to Dox is mediated by regulating DNA repair genes. We further demonstrated that NF-κB1 interacts with FOXM1 in the presence of Dox to protect breast cancer cells from DNA damage. Finally, silencing FOXM1 expression in a mouse xenograft model significantly sensitized the cells to Dox. Our systematic approaches identified an unexpected role of FOXM1 in Dox resistance by regulating DNA repair genes and FOXM1 may be a promising therapeutic target for sensitizing breast cancer cells to Dox. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2962. doi:1538-7445.AM2012-2962
- Published
- 2012
40. Abstract 4283: Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis
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Isaiah J. Fidler, Sang Bae Kim, Ju Seog Lee, Hyun Goo Woo, Sun Jin Kim, Eun Sung Park, Yun-Yong Park, Se-Lyun Yoon, Sun-Hee Leem, Soo Mi Kim, Jae Ho Cheong, Seung Wook Kim, and Gordon B. Mills
- Subjects
Cancer Research ,Microarray ,Cancer ,Biology ,medicine.disease ,Bioinformatics ,Metastasis ,Transcriptome ,Oncology ,Cancer cell ,medicine ,Cancer research ,Epigenetics ,Reprogramming ,Brain metastasis - Abstract
Although the importance of the cellular microenvironment (soil) during invasion and metastasis of cancer cells (seed) has been well-recognized, technical challenges have limited the ability to assess the influence of the microenvironment on cancer cells at the molecular level. Here, we show that an experimental strategy, competitive cross-species hybridization of microarray experiments, can characterize the influence of different microenvironments on cancer cells by independently extracting gene expression data of cancer and host cells when human cancer cells were xenografted into different organ sites of immunocompromised mice. Surprisingly, the analysis of gene expression data showed that the brain microenvironment induces complete reprogramming of metastasized cancer cells, resulting in a gain of neuronal cell characteristics and mimicking neurogenesis during development. We also show that epigenetic changes coincide with transcriptional reprogramming in cancer cells. These observations provide proof of principle for competitive cross-species hybridization of microarray experiments to characterize the effect of the microenvironment on tumor cell behavior Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4283. doi:1538-7445.AM2012-4283
- Published
- 2012
41. Abstract 5142: Up-regulation of glutamine synthetase attenuates the oncogenicity of wnt/β-catenin signaling in hepatocellular carcinoma
- Author
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In Young Park, Sang Bae Kim, Mi-Ra Jeong, Bo Hwa Sohn, Ju Seog Lee, and Yun-Yong Park
- Subjects
Cancer Research ,Gene knockdown ,Cell growth ,Wnt signaling pathway ,Cancer ,Biology ,medicine.disease ,Oncology ,Biochemistry ,Cell culture ,Glutamine synthetase ,Cancer cell ,Cancer research ,medicine ,Intracellular - Abstract
Wnt/β-catenin signaling has been known to be involved in many cellular processes including cell proliferation, migration, and survival. Aberrant activation of Wnt/β-catenin signaling has been widely reported in many cancers and associated with poor outcome after treatments. However, activation of Wnt/β-catenin signaling in hepatocellular carcinoma (HCC) has been known to be significantly associated with favorable outcome. In this study, we identified 82 genes as a β-catenin signature by analyzing expression data from tumor tissues of patients with HCC and liver tissues from active β-catenin mutant transgenic mice. HCC patients with the β-catenin signature have significantly better prognosis in both overall survival and recurrence-free survival than those without the signature. Further analysis of β-catenin signature revealed over-expression of glutamine synthetase (GS), liver-specific β-catenin target gene, and shift of glutamine metabolism. Cell growth rate were highly dependent on GS expression levels. Cell proliferation rate was increased by GS knockdown using shRNAs but decreased by GS overexpression in HCC cell lines. Intracellular glutamate concentrations were severely decreased by GS overexpression. GS overexpression in HCC cells also led to decrease intracellular α-ketoglutarate levels impeding TCA cycle, and intracellular glutathione levels accumulating high reactive oxygen species (ROS). In conclusion, we found GS up-regulation in HCC cells inhibited cell growth by glutamate depletion and thereby lower anaplerotic metabolic activity and higher ROS levels. Our results present molecular mechanisms for the favorable outcome in HCC patients with CTNNB1 mutations and importance of glutamine metabolism in cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5142. doi:1538-7445.AM2012-5142
- Published
- 2012
42. Gene Expression Signature Analysis Identifies Vorinostat as a Candidate Therapy for Gastric Cancer
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Yun Yong Park, Sang Bae Kim, Jae Yong Cho, Jae Yun Lim, Gordon B. Mills, Woonyoung Choi, Sofie Claerhout, Kyounghyun Kim, and Ju Seog Lee
- Subjects
Chromosomal Proteins, Non-Histone ,Cancer Treatment ,lcsh:Medicine ,Kinesins ,Gene Expression ,Hydroxamic Acids ,Biochemistry ,Drug Discovery ,Molecular Cell Biology ,Gene expression ,lcsh:Science ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Vorinostat ,Multidisciplinary ,Cell Death ,Histone deacetylase inhibitor ,Genomics ,Gene Expression Regulation, Neoplastic ,Oncology ,Medicine ,Oncology Agents ,Research Article ,Biotechnology ,medicine.drug ,Drugs and Devices ,Drug Research and Development ,medicine.drug_class ,Blotting, Western ,Antineoplastic Agents ,In Vitro Techniques ,Biology ,Group II Phospholipases A2 ,Molecular Genetics ,Stomach Neoplasms ,Cell Line, Tumor ,Gastrointestinal Tumors ,Genetics ,medicine ,Humans ,Apolipoprotein C-I ,Gene Expression Profiling ,lcsh:R ,Autophagy ,Computational Biology ,Cancers and Neoplasms ,Cancer ,Chemotherapy and Drug Treatment ,medicine.disease ,Histone Deacetylase Inhibitors ,Gene expression profiling ,Gastric Cancer ,Chromobox Protein Homolog 5 ,Gene chip analysis ,Cancer research ,lcsh:Q ,Genome Expression Analysis - Abstract
Background Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future. Methodology/Principal Findings Using microarray technology, we generated a gene expression profile of human gastric cancer–specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern. Conclusions/Significance We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.
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- 2011
43. Abstract 356: Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer
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Jane Li, Ana M. Gonzalez-Angulo, Yun-Yong Park, Stephen Safe, Soo Mi Kim, Ju Seog Lee, Sang Bae Kim, Bryan T. Hennessy, Gordon B. Mills, Kyoungjyun Kim, Jae Yun Lim, Yiling Lu, and Eun Sung Park
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Cancer Research ,Cellular activity ,business.industry ,Regulator ,Cancer ,Estrogen receptor ,medicine.disease ,Bioinformatics ,body regions ,Breast cancer ,Oncology ,Nuclear receptor ,Gene expression ,medicine ,Cancer research ,business ,Estrogen receptor alpha - Abstract
ESR1 is one of the most important oncogenes and therapeutic targets in breast cancer. By applying systems-level re-analysis of publicly available gene expression data, we uncovered potential regulator of ESR1. We demonstrated that orphan nuclear receptor NR2E3 regulates ESR1 via direct binding to the ESR1 promoter with concomitant recruitment of PIAS3 to promoter in breast cancer cells, and is essential for physiological cellular activity of ESR1 in estrogen receptor (ER)-positive breast cancer cells. Moreover, expression of NR2E3 was significantly associated with recurrence-free survival and favorable response to tamoxifen treatment in women with ER-positive breast cancer. Our results provide mechanistic insight into how ESR1 is regulated by NR2E3 and clinical relevance of NR2E3 in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 356. doi:10.1158/1538-7445.AM2011-356
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- 2011
44. Abstract 3995: Identification of putative miRNA targets by a systems biological approach in NCI-60 data
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Bo-Hwa Sohn, Sang Bae Kim, Eun-Sung Park, Ju Seog Lee, Sang-Cheol Oh, Michael A. Davis, Jong Seung Kim, Yun-Yong Park, Gordon B. Mills, and Soo-Mi Kim
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Genetics ,Cancer Research ,Messenger RNA ,Cancer ,RNA ,Genomics ,Biology ,Proteomics ,medicine.disease ,Correlation ,Oncology ,microRNA ,Gene expression ,medicine - Abstract
MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules and on average only 22 nucleotides long that regulate gene expression at the post-transcriptional level. Target predictions of miRNA based on sequence are limited due to too many candidates resulting in high false positives. To overcome this limitation functional target prediction approaches have been investigated by using mRNA and miRNA expression data. These approaches used in the computational assessment of functional miRNA-target association. However, these approaches with miRNA-mRNA association were not enough to verify real functional targets at protein level, which could affect on biological signaling pathway. Therefore, in order to overcome current limitation we developed a novel correlation-based approach (sequence-independence) that predict the association of miRNAs with signaling pathways by using genomics and proteomics data from NCI-60 cancer cell lines (mRNA, miRNA, and protein expression data). To identify miRNA-protein association, we used two correlation-based methods: direct comparison (miRNA-protein pairs) and indirect comparison (miRNA-mRNA and protein-mRNA pairs), then compared their outputs. In direct comparison, we calculated Pearson correlation coefficients for 96k probe pairs and found over 3 k significant correlated pairs (3.2 %) at the cut-off p-value < 0.005: among them 53.4 % were negative and 46.6% were positive. In indirect comparison, we ranked the number of correlated mRNA probes between miRNA-mRNA and protein-mRNA pairs, in which we calculated over 11 and 5.7 million probe pairs respectively. Then, two significant output pair sets were combined by intersection of mRNA probes and then determined the number of common probes. With these determined numbers, finally we generated association score matrix between miRNA and protein probes. Using those score matrix, we evaluated the highly associated miRNAs with 40 biological pathways, which play critical roles in cell cycle, proliferation and metastasis. In conclusion, we developed a noble expression profile-based approach to systematically predict potential miRNA functional targets which play critical roles in cell signaling pathways from the NCI-60 genomic and proteomic data at whole genomic scale. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3995. doi:10.1158/1538-7445.AM2011-3995
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- 2011
45. A Case of Visual and Auditory Hallucinations during Intravenous Voriconazole Therapy
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Sung-Yeon Cho, Min Ju Kim, M Lee, Dong-Gun Lee, Jae-Cheol Kwon, Yul Hee Cho, Moon-Hee Youn, Si-Hyun Kim, Sang-Bae Kim, and Yoo-Jin Kim
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Voriconazole ,medicine.diagnostic_test ,business.industry ,Aspergillosis ,medicine.disease ,Fungal pneumonia ,Pharmacotherapy ,Therapeutic drug monitoring ,Amphotericin B deoxycholate ,Anesthesia ,medicine ,Trough level ,business ,Adverse effect ,medicine.drug - Abstract
Voriconazole is a triazole with broad spectrum antifungal activity, and it is currently considered to be the first-line agent for the treatment of invasive aspergillosis. We report here on a case of visual and auditory hallucinations during intravenous treatment with voriconazole in association with a high trough level. A 28-year-old man with acute myelogenous leukemia was admitted for re-induction remission chemotherapy. During the persistent neutropenic fever, intravenous voriconazole was administered for the suspected invasive fungal pneumonia. He began to have visual hallucinations on the 1st day and auditory hallucinations on the 3rd day of voriconazole therapy. The plasma peak and trough concentration levels of voriconazole were 9.9 and 7.4 μg/ml, respectively, on the 3rd day. The hallucinations resolved after changing to amphotericin B deoxycholate, and the plasma concentration of voriconazole dropped to less than 0.5 μg/ml. The genotype of the CYP2C19 alleles was classified as a heterozygous extensive metabolizer. We suggest that therapeutic drug monitoring of voriconazole is indicated for a case that is suspicious for a voriconazole-related adverse event.
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- 2011
46. Abstract 2005: The evolutionarily conserved gene expression signatures SPARC and SPP1 are genetic determinants of progression from Barrett's esophagus to esophageal adenocarcinoma
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Xifeng Wu, Kenneth K. Wang, Jeffrey H. Lee, Jaffer A. Ajani, Manoop S. Bhutani, Yun-Yong Park, Jae Yong Cho, Sang Bae Kim, Soo Mi Kim, Julie G. Izzo, Navtej S. Buttar, Eun Sung Park, and Ju Seog Lee
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Cancer Research ,Microarray ,Cancer ,Inflammation ,Disease ,Biology ,Bioinformatics ,medicine.disease ,Pathogenesis ,Oncology ,Barrett's esophagus ,Gene expression ,Cancer research ,medicine ,medicine.symptom ,Gene - Abstract
Esophageal adenocarcinoma (EAC) is thought to arise from the metaplastic condition known as Barrett's esophagus (BE), which is caused by chronic inflammation due to gastroesophageal reflux disease. Since the molecular mechanisms underlying the pathogenesis of EAC are unknown, understanding EAC development mechanisms and their regulation is crucial for the treatment of EAC. Comparative genomic studies of evolutionarily similar and dissimilar species have been suggested as a means of studying the evolutionary biology in the species. Thus, we performed a cross-species comparison of gene expression patterns in human and rat tissues, uncovering the evolutionarily conserved gene expression patterns during EAC progression across both species. Using a non-carcinogenic rat model that progresses from normal esophagus to BE to EAC, we were able to identify the biological mechanisms of EAC development. We analyzed gene expression data from rat specimens (15 NE, 18 BE, and 30 EAC) as well as from human tissues (28NE, 72BE, and 75EAC). Using the presence of orthologous genes in both microarray platforms and various statistical tests, we uncovered a number of genes whose expression patterns were well conserved during progression from NE to BE in humans and rats. The expression of 869 genes was commonly altered when NE progressed to BE in both humans and rats (P During BE to EAC progression in both species, 541 gene expressions were altered (P In conclusion, systems-level characterization of gene expression data from humans and a rodent model shows evolutionarily conserved genes and pathways during EAC progression, and these genes and pathways could become reliable biomarkers for early detection, or therapeutic targets for the treatment of EAC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2005.
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- 2010
47. Abstract 546: Characterization of tumor-stromal interactions in microenvironment of prostate cancer bone metastasis
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Zhi Gang Li, Nora M. Navone, Soo Mi Lim, Yun-Yong Park, Sang Bae Kim, Ju Seog Lee, and Jun Yang
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PCA3 ,Cancer Research ,Pathology ,medicine.medical_specialty ,Stromal cell ,Bone metastasis ,Cancer ,Chromoplexy ,Biology ,medicine.disease ,Prostate cancer ,Oncology ,Cancer stem cell ,Bone cell ,medicine - Abstract
Prostate cancer is the most common cancer in men around the world, with a high incidence of bone metastasis, which is the major determinant of mortality in prostate cancer. The survival and proliferation of prostate cancer cells metastatic to bone result from the cross-talk between carcinoma cells and the stromal cells. In contrast to skeletal metastases resulting from breast or lung cancer that are most often osteolytic, metastases from prostate carcinoma are nearly always osteoblastic, suggesting that interactions between prostate cancer cells and stroma in bone might be different from those of lung or breast cancer cells and bone stroma. Therefore, gene expression patterns that are unique to osteoblastic prostate cancer will help to identify genes involved in the bidirectional cross-talk between prostate cancer cells and bone cells in microenvironment niche. However, because gene expression signatures from human cancer tissues are a mixture of those from carcinoma and stromal cells, it has been impossible to delineate stromal cell specific gene expression signatures from carcinoma cell signatures. Thus, we have devised a novel experimental strategy: “competitive cross-species hybridization of microarray”, which can simultaneously extract gene expression patterns of carcinoma cells and stromal cells from a single xenograft sample. In the current study, we xenografted human prostate cancer cells (PC3, PCA118b, 10A) into mouse bone and prostate and used these tissues for microarray experiments. Total RNAs were purified from three different tissue groups: normal bones (mouse RNA only), tumor-bearing bones (mixture of mouse and human RNA), and tumor-bearing prostates (mixture of mouse and human RNA). Labeled cRNA from normal bones and tumor-bearing bones were hybridized to mouse microarray slide to measure gene expression of mouse bone cells. Likewise, labeled cRNA from tumor-bearing prostate and tumor-bearing bone were hybridized to human microarray slide to measure gene expression of human prostate cancer cells. Gene expression data from mouse microarrays identified gene expression patterns unique to bone cells that interact with prostate cancer cells in bone. When same analysis applied to human data, it also uncovered prostate cancer cell gene expression signatures associated with different microenvironment (prostate vs. bone). In order to uncover gene networks involved in cross-talk between prostate cancer cells and bone cells in metastatic bone microenvironment, gene network analysis using Ingenuity Pathway Analysis (IPA) was applied to combined gene lists from human and mouse data. In conclusion, by applying novel experimental strategy, “competitive cross-species hybridization of microarray”, we uncovered critical gene network involved in bidirectional cellular communication that drives the survival of prostate cancer cells in metastatic bone microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 546.
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- 2010
48. Abstract 4266: Potential role of reactive oxygen species in affecting tumorigenicity of glioblastoma stem cells
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Peng Huang, Ju Seog Lee, Gang Chen, Li Feng, Shu-Qiang Yuan, Howard Colman, Naima Hammodi, Rui-Hua Xu, Sang Bae Kim, and Feng Wang
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Cancer Research ,Programmed cell death ,Cancer ,Biology ,medicine.disease ,Oncology ,Cell culture ,Cancer stem cell ,Neurosphere ,Immunology ,Cancer cell ,Cancer research ,medicine ,Viability assay ,Stem cell - Abstract
Glioblastoma multiforme (GBM) is a common and highly aggressive primary brain tumor with poor prognosis due in part to drug resistance and high incidence of tumor recurrence. The drug resistant and cancer recurrence phenotype may be ascribed to the presence of cancer stem cells, which seem to reside in special stem-cell niches in vivo and require special culture conditions including certain growth factors and serum-free medium to maintain their stemness in vitro. In this study, we used two lines of stem-like cancer cells (GSC11 and GSC23) derived from the tumor tissues of two GBM patients by classical neurosphere culture system, and showed that addition of serum (FBS) to the medium induced an increase of ROS, leading to aberrant differentiation and eventual cell death. Although both GBM stem-like cell lines showed high percentage of CD133-positive cells (20% in GSC11 and 70% in GSC23), exposure to serum only caused a moderate decrease of CD133 expression at later time points. Several methods were used to further test the role of ROS in affecting the stemness of the GSC cells and their self-renewal capacity. Addition of 5% FBS or removal of the antioxidant supplements (B27) from the culture medium caused the spheroid GSC cells to attach to the culture surface, exhibit differentiation morphology, decrease expression of certain stem-cell markers, and eventually die within two weeks. Serum exposure also resulted in a decrease of the GSC ability to form colonies in soft agar assay and to grow tumors in a mouse xenograft model. Although an increase of general cellular ROS could be detected when GSC cells were exposed to FBS, the mitochondrial superoxide appeared to be prominent and likely to be a primary event, which led to a compensatory increase of the mitochondrial SOD2 expression and upregulation of glutathione synthesis. Interestingly, addition of the antioxidant N-Acetylcysteine to the FBS-containing medium partially blocked the FBS-induced aberrant differentiation and improved cell viability and self-renewal capacity, suggesting that ROS may play an important role in affecting stemness and differentiation status of the cancer stem cells. We postulate that during tumor development, only the progeny cells that acquire the ability to counteract the impact of ROS increase induced by serum may eventually proliferate and grow as the tumor bulk, and that proper redox-modulation may be a potential novel strategy to block tumor formation and possibly kill the stem-like cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4266.
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- 2010
49. Association of YAP1 activation with poor patient prognosis and effect on chemoresistance in gastric cancer
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Wonkyung Jung, Sang Bae Kim, Jae Yun Lim, Sang Cheul Oh, Sangho Lee, You-Jin Jang, Bo Hwa Sohn, Sung Sook Lee, Jae Ho Cheong, Sung Hoon Noh, Ju Seog Lee, Yun-Yong Park, Keun-Wook Lee, Eun Sung Park, Woojin Jeong, Jaffer A. Ajani, Jae Yong Cho, Patrick Tan, Young-Jae Mok, and Baek-hui Kim
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YAP1 ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,Clinical heterogeneity ,medicine ,Cancer ,medicine.disease ,Bioinformatics ,business - Abstract
4113 Background: Clinical heterogeneity in gastric cancer is likely due to biological differences among patients. Molecular subtypes and their associated biomarkers need to be established to improve treatment of this disease. We aimed to uncover subgroups of gastric cancer that have distinct biological characteristics associated with clinical outcome and to identify potential best treatments or therapeutic targets for each subgroup. Methods: We analyzed gene expression profiling data from gastric cancer cell lines and 267 patients with gastric cancer to uncover tumor subtypes and identify a gene expression signature associated with prognosis and response to adjuvant chemotherapy. The association of the signature with prognosis was validated in an independent cohort of 200 patients, and its association with response to adjuvant therapy was validated by cell culture experiments. Results: We identified an expression signature of 88 genes that specifically reflected activation of the oncogene YAP1. Compared with patients without this signature, patients with the YAP1 signature had significantly poorer prognosis. In multivariate analysis, the signature was the strongest indicator of overall survival among all demographic and clinical variables examined together (hazard ratio, 2.1; 95% confidence interval, 1.3-3.3;P = .002). Activation of YAP1 was significantly associated with resistance to adjuvant chemotherapy. We also demonstrated that the Notch pathway is a potential therapeutic target for overcoming chemoresistance mediated by YAP1. Conclusions: Activation of the oncogene YAP1 is significantly associated with poorer survival of patients with gastric cancer and induces chemoresistance to this disease. Therefore, YAP1 may be highly attractive therapeutic target for patients with gastric cancer resistant to standard chemotherapy.
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