30 results on '"Chun-Chia Cheng"'
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2. Irradiation suppresses STAT3-mediated MCL1 expression to augment CD8+ T cells cytotoxicity against EGFR-positive lung cancer
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Chun-I Wang, Yi-Fang Chang, Zong-Lin Sie, Chun-Chia Cheng, and Ai-Sheng Ho
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biology ,Chemistry ,business.industry ,medicine.disease ,Text mining ,Cancer research ,biology.protein ,medicine ,Cytotoxic T cell ,MCL1 ,Augment ,Cytotoxicity ,STAT3 ,Lung cancer ,business - Abstract
Background Tumor cells progress to evade immunological attacks and prohibit activity of CD8+ T cells. Irradiation damages tumor cells and augments tumor immunotherapy in clinical application. However, the detail mechanism remains elusive. We aimed to uncover the mechanism of irradiation augmenting cytotoxic CD8+ T cells to suppress tumor progression in non-small-cell lung cancer (NSCLC). Methods EGFR-positive NSCLC cell lines were co-cultured with isolated PBMCs from healthy volunteers, cell viability and apoptosis were measured. RNAseq was used to screen the IFNγ-mediated gene expression in A549 cells. Irradiation was used to augment PBMCs-mediated anti-tumor effect and the irradiation effect to IFNγ-mediated gene expression was investigated using qPCR and Western blots. Results Co-culture of tumor cells stimulates increase of granzyme B and IFNγ in CD8+ T, but A549 exhibits resistance against CD8+ T cytotoxicity. Irradiation inhibits A549 proliferation and enhances apoptosis, augmenting PBMCs-mediated cytotoxicity against A549. IFNγ simultaneously increased phosphorylation on STAT1 and STAT3 in EGFR-positive lung cancer, resulting in overexpression of PD-L1. In RNAseq analysis, MCL1 was identified and increased by IFNγ-STAT3 axis in A549 cells, we found that irradiation specifically inhibits phosphorylation on STAT1 and STAT3 in IFNr-treated A549, resulting in reductions of PD-L1 and MCL1. Moreover, knockdowns of STAT3 and MCL1 increased PBMCs against irradiated A549 cells. Conclusion This study demonstrated that A549 expressed MCL1 against CD8+ T cell-mediated apoptosis. In addition, we found that irradiation suppressed STAT3 phosphorylation and IFNγ-mediated PD-L1 and MCL1 expression, revealing a potential mechanism of irradiation augmenting immune surveillance.
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- 2021
3. Low molecular weight fucoidan inhibits hepatocarcinogenesis and nonalcoholic fatty liver disease in zebrafish via ASGR/STAT3/HNF4A signaling
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Szu-Yuan Wu, Chun-Chia Cheng, Chiou-Hwa Yuh, Suat-Ming Chan, Bonifasius Putera Sampurna, Kuan-Hao Lin, and Wan-Yu Yang
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0301 basic medicine ,Medicine (General) ,Transgene ,Medicine (miscellaneous) ,Protein transporter activity ,03 medical and health sciences ,R5-920 ,0302 clinical medicine ,therapeutics ,medicine ,oligo‐fucoidan ,Zebrafish ,Research Articles ,Gene knockdown ,biology ,Chemistry ,hepatocellular carcinoma ,zebrafish ,medicine.disease ,biology.organism_classification ,digestive system diseases ,Cell biology ,HBx ,030104 developmental biology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Asialoglycoprotein receptor ,Liver cancer ,Research Article ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Background Hepatocellular carcinoma ranks fourth in cancer‐related mortality currently lacks effective therapeutics. Fucoidan is sulfated polysaccharide that is mainly found in brown seaweeds. In this study, we investigated the effects and mechanisms of low molecular weight fucoidan (i.e. oligo‐fucoidan [OF]) preventing hepatocarcinogenesis. Methods We used [HBx,src], [HBx,src,p53−/+], and [CD36] transgenic zebrafish liver cancer model treated with OF, and performed molecular and histopathological analysis. Transcriptomic and pathways analysis was performed. Results Decreased expression of lipogenic enzymes, fibrosis markers, and cell cycle/proliferation markers by OF in [HBx,src] and [HBx,src,p53−/+] transgenic fish. Liver fibrosis was decreased as revealed by Sirius Red staining, and the liver cancer formation was eventually reduced by feeding OF. OF was also found to be capable of reducing lipid accumulation and cancer formation in non‐B non‐C Hepatocellular carcinoma (HCC) model in CD36 transgenic zebrafish. Whole‐genome expression analysis showed that 661 genes were up‐regulated, and 451 genes were downregulated by feeding OF. Upregulated genes were mostly found in protein transporter activity, and downregulated genes were enriched with response to extracellular stimulus and metal binding in gene ontology analysis. The driver gene was HNF4A revealed by NetworkAnalyst from OF differential regulated genes at various insults. OF is able to bind the asialoglycoprotein receptor (ASGR) in hepatoma cells, and increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in both hepatoma cells and [HBx,src,p53−/+] transgenic fish liver cancer model. Using chromatin‐immunoprecipitation, we found pSTAT3 could associate with the P1 promoter of HNF4A. Knockdown of either ASGR or HNF4A reversed OF mediated anti‐cancer cell proliferation. Conclusions Taken together, we provide evidence that OF exhibits the anti‐HCC, anti‐steatosis, and anti‐fibrosis effect for liver in zebrafish models, and the anti‐cancer potential of OF attributed to the binding to ASGR and activation of STAT3/HNF4A signaling. OF might be potentially valuable for the management of HCC., We used zebrafish preclinical model and whole‐genome transcriptome analysis to understand the mechanisms for oligo‐fucoidan anti‐HCC effect.Oligo‐fucoidan binds to ASGR receptor on hepatocyte.Oligo‐fucoidan activates the phosphorylation of STAT3, which binds to the P1 promoter of HNF4A, transcriptionally regulates P1‐isoform HNF4A expression.Oligo‐fucoidan prevents steatosis, fibrosis and HCC formation in HBx,src,p53−/+, diet induced obesity and CD36 transgenic fish.
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- 2020
4. Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres
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Po-Jui Hsu, Zong-Lin Sie, Fang-Hsin Chen, and Chun-Chia Cheng
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0301 basic medicine ,Carcinogenesis ,Colorectal cancer ,General Chemical Engineering ,Disease ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,HT29 Cells ,0302 clinical medicine ,Cancer stem cell ,Cell Line, Tumor ,Spheroids, Cellular ,medicine ,Humans ,General Immunology and Microbiology ,General Neuroscience ,LGR5 ,Cancer ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Neoplastic Stem Cells ,Cancer research ,Colorectal Neoplasms - Abstract
Cancer stem cells play a vital role against clinical therapies, contributing to tumor relapse. There are many oncogenes involved in tumorigenesis and the initiation of cancer stemness properties. Since gene expression in the formation of colorectal cancer-derived tumorspheres is unclear, it takes time to discover the mechanisms working on one gene at a time. This study demonstrates a method to quickly discover the driver genes involved in the survival of the colorectal cancer stem-like cells in vitro. Colorectal HT29 cancer cells that express the LGR5 when cultured as spheroids and accompany an increase CD133 stemness markers were selected and used in this study. The protocol presented is used to perform RNAseq with available bioinformatics to quickly uncover the overexpressed driver genes in the formation of colorectal HT29-derived stem-like tumorspheres. The methodology can quickly screen and discover potential driver genes in other disease models.
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- 2020
5. Low Molecular Weight Fucoidan Prevents Radiation-Induced Fibrosis and Secondary Tumors in a Zebrafish Model
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Szu-Yuan Wu, Chun-Chia Cheng, Chiou-Hwa Yuh, Wan-Yu Yang, Hsiao Ming-Chen, Hua-Kuo Lin, Kuan-Hao Lin, and Shin-Lin Tsai
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0301 basic medicine ,Cancer Research ,radiation-induced secondary malignancy ,H&E stain ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Fibrosis ,Gene expression ,medicine ,Sirius Red ,Zebrafish ,biology ,Fucoidan ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,biology.organism_classification ,medicine.disease ,zebrafish ,radiation-induced fibrosis ,HBx ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Oligo-Fucoidan ,Liver cancer - Abstract
Radiotherapy often causes unwanted side effects such as radiation-induced fibrosis and second malignancies. Fucoidan, a sulfated polysaccharide extracted from brown seaweed, has many biological effects including anti-inflammation and anti-tumor. In the present study, we investigated the radioprotective effect of Oligo-Fucoidan (OF) using a zebrafish animal model. Adult zebrafish of wild-type and transgenic fish with hepatocellular carcinoma were orally fed with Oligo-Fucoidan before irradiation. Quantitative PCR, Sirius red stain, hematoxylin, and eosin stain were used for molecular and pathological analysis. Whole genomic microarrays were used to discover the global program of gene expression after Oligo-Fucoidan treatment and identified distinct classes of up- and downregulated genes/pathways during this process. Using Oligo-Fucoidan oral gavage in adult wild-type zebrafish, we found Oligo-Fucoidan pretreatment decreased irradiation-induced fibrosis in hepatocyte. Using hepatitis B virus X antigen (HBx), Src and HBx, Src, p53&minus, /+ transgenic zebrafish liver cancer model, we found that Oligo-Fucoidan pretreatment before irradiation could lower the expression of lipogenic factors and enzymes, fibrosis, and cell cycle/proliferation markers, which eventually reduced formation of liver cancer compared to irradiation alone. Gene ontology analysis revealed that Oligo-Fucoidan pretreatment increased the expression of genes involved in oxidoreductase activity in zebrafish irradiation. Oligo-Fucoidan also decreased the expression of genes involved in transferase activity in wild-type fish without irradiation (WT), nuclear outer membrane-endoplasmic reticulum membrane network, and non-homologous end-joining (NHEJ) in hepatocellular carcinoma (HCC) transgenic fish. Rescue of those genes can prevent liver cancer formation. Conclusions: Our results provide evidence for the ability of Oligo-Fucoidan to prevent radiation-induced fibrosis and second malignancies in zebrafish.
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- 2020
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6. Anti-angiogenic treatment (Bevacizumab) improves the responsiveness of photodynamic therapy in colorectal cancer
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Tsai-Yueh Luo, Ying-Hsia Shih, Ping-Fang Chiang, Hua-Ching Lin, Wei-Lun Chiang, Cheng-Liang Peng, Ming-Jium Shieh, and Chun-Chia Cheng
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Vascular Endothelial Growth Factor A ,0301 basic medicine ,Bevacizumab ,Combination therapy ,Colorectal cancer ,Angiogenesis ,medicine.medical_treatment ,Biophysics ,Angiogenesis Inhibitors ,Enzyme-Linked Immunosorbent Assay ,Photodynamic therapy ,Kaplan-Meier Estimate ,Dermatology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,polycyclic compounds ,Animals ,Medicine ,Pharmacology (medical) ,Mice, Inbred BALB C ,Photosensitizing Agents ,Dose-Response Relationship, Drug ,Neovascularization, Pathologic ,business.industry ,Cancer ,medicine.disease ,eye diseases ,Tumor Burden ,Vascular endothelial growth factor ,Disease Models, Animal ,Receptors, Vascular Endothelial Growth Factor ,030104 developmental biology ,Mesoporphyrins ,Photochemotherapy ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,Drug Therapy, Combination ,Female ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
Photodynamic therapy (PDT) is a treatment utilizing the combined action of photosensitizers and light for the treatment of various cancers. The mechanisms for tumor destruction after PDT include direct tumor cell kill by singlet oxygen species (OS), indirect cell kill via vascular damage, and an elicited immune response. However, it has been reported that many cellular activators, including vascular endothelial growth factor (VEGF), are produced by tumor cells after PDT. In this study, we demonstrate that meta-tetra(hydroxyphenyl) chlorin (mTHPC)-based photodynamic therapy combined with bevacizumab (Avastin™), an anti-VEGF neutralizing monoclonal antibody that blocks the binding of VEGF to its receptor, can enhance the effectiveness of each treatment modality. We evaluated the efficacy of bevacizumab-based anti-angiogenesis in combination with PDT as well as the resulting VEGF levels and microvessel density (MVD) in a mouse model of human colon cancer. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were performed to assess VEGF concentrations and microvessel density in the various treatment groups, and confocal imaging and high performance liquid chromatography (HPLC) analyses were used to measure the distribution and concentration of mTHPC in tumors. Our results demonstrate that combination of PDT followed by bevacizumab significantly elicits a greater tumor response whereas bevacizumab treatment prior to PDT led to a reduced tumor response. Immunostaining and ELISA analyses revealed a lower expression of VEGF in tumors treated with combination therapy of PDT followed by bevacizumab. However, bevacizumab treatment decreased the accumulation of mTHPC in tumors 24 h after administration, which complemented the results of decreased anti-tumor efficacy of bevacizumab followed by PDT.
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- 2018
7. STAT3 exacerbates survival of cancer stem-like tumorspheres in EGFR-positive colorectal cancers: RNAseq analysis and therapeutic screening
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Ai Sheng Ho, Yu-Cheng Chang, Ya Wen Chiang, Bi Ling Yang, Chun Chao Chang, Po Nien Liao, Yi Fang Chang, Ken-Hong Lim, Jungshan Chang, Ying Wen Su, Caleb Gon-Shen Chen, Huan Chau Lin, and Chun Chia Cheng
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STAT3 Transcription Factor ,0301 basic medicine ,Colorectal cancer ,Endocrinology, Diabetes and Metabolism ,EGFR ,Clinical Biochemistry ,lcsh:Medicine ,Biology ,PDGFA ,STAT3 ,03 medical and health sciences ,Wnt ,LGR5 ,Cancer stem cell ,Epidermal growth factor ,medicine ,Humans ,Pharmacology (medical) ,Phosphorylation ,Wnt Signaling Pathway ,Molecular Biology ,Early Detection of Cancer ,Platelet-Derived Growth Factor ,Epidermal Growth Factor ,Sequence Analysis, RNA ,Research ,Biochemistry (medical) ,lcsh:R ,Wnt signaling pathway ,Cancer ,Cell Biology ,General Medicine ,medicine.disease ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Homoharringtonine ,Neoplastic Stem Cells ,Cancer research ,Stem cell ,Colorectal Neoplasms ,HT29 Cells - Abstract
Background Cancer stem cells are capable of undergoing cell division after surviving cancer therapies, leading to tumor progression and recurrence. Inhibitory agents against cancer stem cells may be therapeutically used for efficiently eradicating tumors. Therefore, the aim of this study was to identify the relevant driver genes that maintain cancer stemness in epidermal growth factor receptor (EGFR)-positive colorectal cancer (CRC) cells and to discover effective therapeutic agents against these genes. Methods In this study, EGFR-positive cancer stem-like cells (CSLCs) derived from HCT116 and HT29 cells were used as study models for in vitro inductions. To identify the differential genes that maintain CSLCs, RNAseq analysis was conducted followed by bioinformatics analysis. Moreover, a panel containing 172 therapeutic agents targeting the various pathways of stem cells was used to identify effective therapeutics against CSLCs. Results RNAseq analysis revealed that 654 and 840 genes were significantly upregulated and downregulated, respectively, in the HCT116 CSLCs. Among these genes, notably, platelet-derived growth factor A (PDGFA) and signal transducer and activator of transcription 3 (STAT3) were relevant according to the cancer pathway analyzed using NetworkAnalyst. Furthermore, therapeutic screening revealed that the agents targeting STAT3 and Wnt signaling pathways were efficient in reducing the cell viabilities of both HCT116 and HT29 cells. Consequently, we discovered that STAT3 inhibition using homoharringtonine and STAT3 knockdown significantly reduced the formation and survival of HT29-derived tumorspheres. We also observed that STAT3 phosphorylation was regulated by epidermal growth factor (EGF) to induce PDGFA and Wnt signaling cascades. Conclusions We identified the potential genes involved in tumorsphere formation and survival in selective EGFR-positive CRCs. The results reveal that the EGF-STAT3 signaling pathway promotes and maintains CRC stemness. In addition, a crosstalk between STAT3 and Wnt activates the Wnt/β-catenin signaling pathway, which is also responsible for cancer stemness. Thus, STAT3 is a putative therapeutic target for CRC treatment. Electronic supplementary material The online version of this article (10.1186/s12929-018-0456-y) contains supplementary material, which is available to authorized users.
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- 2018
8. EGFR-mediated interleukin enhancer-binding factor 3 contributes to formation and survival of cancer stem-like tumorspheres as a therapeutic target against EGFR-positive non-small cell lung cancer
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Jungshan Chang, Kuei Fang Chou, Cheng Liang Peng, Nai Wen Su, Ying Wen Su, Chun Chia Cheng, Ken-Hong Lim, Cheng-Wen Wu, Yi Fang Chang, Ai Sheng Ho, Yu-Cheng Chang, Huan Chau Lin, Caleb Gon-Shen Chen, Bi Ling Yang, and Ya Wen Chiang
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Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Cancer Research ,Lung Neoplasms ,Afatinib ,Mice, SCID ,Mice ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,Mice, Inbred NOD ,Cancer stem cell ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,ERBB3 ,Molecular Targeted Therapy ,Epidermal growth factor receptor ,Phosphorylation ,Nuclear Factor 90 Proteins ,Lung cancer ,Protein Kinase Inhibitors ,biology ,business.industry ,Cell growth ,Imidazoles ,Cancer ,Drug Synergism ,medicine.disease ,Xenograft Model Antitumor Assays ,ErbB Receptors ,030104 developmental biology ,Oncology ,A549 Cells ,030220 oncology & carcinogenesis ,Cancer cell ,Neoplastic Stem Cells ,Cancer research ,biology.protein ,business ,Naphthoquinones ,medicine.drug - Abstract
Objectives YM155, an inhibitor of interleukin enhancer-binding factor 3 (ILF3), significantly suppresses cancer stemness property, implying that ILF3 contributes to cell survival of cancer stem cells. However, the molecular function of ILF3 inhibiting cancer stemness remains unclear. This study aimed to uncover the potential function of ILF3 involving in cell survival of epidermal growth factor receptor (EGFR)-positive lung stem-like cancer, and to investigate the potential role to improve the efficacy of anti-EGFR therapeutics. Materials and methods The association of EGFR and ILF3 in expression and regulations was first investigated in this study. Lung cancer A549 cells with deprivation of ILF3 were created by the gene-knockdown method and then RNAseq was applied to identify the putative genes regulated by ILF3. Meanwhile, HCC827- and A549-derived cancer stem-like cells were used to investigate the role of ILF3 in the formation of cancer stem-like tumorspheres. Results We found that EGFR induced ILF3 expression, and YM155 reduced EGFR expression. The knockdown of ILF3 reduced not only EGFR expression in mRNA and protein levels, but also cell proliferation in vitro and in vivo, demonstrating that ILF3 may play an important role in contributing to cancer cell survival. Moreover, the knockdown and inhibition of ILF3 by shRNA and YM155, respectively, reduced the formation and survival of HCC827- and A549-derived tumorspheres through inhibiting ErbB3 (HER3) expression, and synergized the therapeutic efficacy of afatinib, a tyrosine kinase inhibitor, against EGFR-positive A549 lung cells. Conclusion This study demonstrated that ILF3 plays an oncogenic like role in maintaining the EGFR-mediated cellular pathway, and can be a therapeutic target to improve the therapeutic efficacy of afatinib. Our results suggested that YM155, an ILF3 inhibitor, has the potential for utilization in cancer therapy against EGFR-positive lung cancers.
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- 2018
9. SPECT imaging evaluation of 111indium-chelated cetuximab for diagnosing EGFR-positive tumor in an HCT-15-induced colorectal xenograft
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Chun Yeh, Hao Jhih Yang, Hua Ching Lin, Yi Fang Chang, Chun Chia Cheng, Kang Wei Chang, Chun Chao Chang, Bin Bin Shih, and Ai Sheng Ho
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0301 basic medicine ,Oncology ,Biodistribution ,medicine.medical_specialty ,medicine.drug_class ,Colorectal cancer ,Cetuximab ,111Indium ,Monoclonal antibody ,Colorectal adenocarcinoma ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Spect imaging ,medicine ,Chelation ,Epidermal growth factor receptor ,neoplasms ,lcsh:R5-920 ,biology ,business.industry ,Cell growth ,General Medicine ,medicine.disease ,digestive system diseases ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,lcsh:Medicine (General) ,business ,medicine.drug - Abstract
Background Epidermal growth factor receptor (EGFR) overexpressed in colorectal cancer (CRC) is a tumor target for developing the anti-tumor theranostic agents. Cetuximab, an anti-EGFR monoclonal antibody against EGFR-positive tumors, inhibits cell proliferation and growth was labeled with radioactive 111indium (111In) in this study for diagnosing EGFR-positive CRC. The aim of this study was to evaluate the efficacy of noninvasive nuclear imaging agent 111In-cetuximab and investigate the biological distribution of 111In-cetuximab in the HCT-15-induced EGFR-positive CRC tumor xenografts. Methods We conjugated cetuximab with an isotope chelator, diethylene triamine penta acetic acid (DTPA), and consequently labeled cetuximab-DTPA with 111In and measured the labeling efficacy by an instant thin layer chromatography (iTLC). Furthermore, the 111In-cetuximab was investigated and compared for imaging small (50 mm3) and large (250 mm3) tumor of CRC xenografts, respectively. Results The conjugated ratio between cetuximab and DTPA was 1:6 measured by MALDI-TOF-MS. The better labeling concentration of cetuximab with 10 mCi of 111In was calculated and experimented as 48 μg, resulting in labeling efficacy >80% detected by iTLC. The results revealed that the 111In-cetuximab accumulated in the both sizes of tumors as a reliable noninvasive diagnostic agent, whereas the ratio of tumor to muscle in the large tumor was 7.5-fold. The biodistribution data indicated that the 111In-cetuximab bound to tumor specifically that was higher than that in other organs. Conclusion We suggested that the 111In-cetuximab was potential for early diagnosis and prognostic monitor of EGFR-positive CRC in further clinical practice.
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- 2017
10. Germline variations at JAK2, TERT, HBS1L-MYB and MECOM and the risk of myeloproliferative neoplasms in Taiwanese population
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Ling Huang, Yi-Hao Chiang, Yi-Fang Chang, Johnson Lin, Yuan-Yeh Kuo, Yu-Cheng Chang, Ming-Chih Chang, Chun-Chia Cheng, Ken-Hong Lim, Nai-Wen Su, Wei-Ting Wang, Caleb Gon-Shen Chen, Wen-Chien Chou, Ruey-Kuen Hsieh, Huan-Chau Lin, and I Cheng
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Oncology ,Gerontology ,medicine.medical_specialty ,education.field_of_study ,Hematology ,MECOM ,business.industry ,Essential thrombocythemia ,Haplotype ,Population ,Single-nucleotide polymorphism ,medicine.disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Polycythemia vera ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business ,Myelofibrosis ,education ,030215 immunology - Abstract
// Yi-Hao Chiang 1, 2, * , Yu-Cheng Chang 1, 2, 3 * , Huan-Chau Lin 1, 2 , Ling Huang 2 , Chun-Chia Cheng 1, 2 , Wei-Ting Wang 1 , Hung-I Cheng 4 , Nai-Wen Su 1, 2, 3 , Caleb Gon-Shen Chen 1, 2, 3, 5 , Johnson Lin 1, 2 , Yi-Fang Chang 1, 2, 3 , Ming-Chih Chang 1, 2, 3 , Ruey-Kuen Hsieh 1, 2 , Wen-Chien Chou 6, 7 , Ken-Hong Lim 1, 2, 3, 8 and Yuan-Yeh Kuo 8 1 Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan 2 Laboratory of Good Clinical Research Center, Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan 3 Department of Medicine, MacKay Medical College, New Taipei City, Taiwan 4 Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, Hsinchu, Taiwan 5 Institute of Molecular and Cellular Biology, National Tsing-Hua University, Hsinchu, Taiwan 6 Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan 7 Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan 8 Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan * Co-first authors, these authors contributed equally to this work Correspondence to: Ken-Hong Lim, email: khlim@mmh.org.tw Yuan-Yeh Kuo, email: yykuo@ntu.edu.tw Keywords: JAK2, TERT, myeloproliferative neoplasms, single nucleotide polymorphism Received: September 16, 2016 Accepted: June 09, 2017 Published: July 12, 2017 ABSTRACT Germline variations at JAK2 , TERT , HBS1L - MYB and MECOM have been found to associate with myeloproliferative neoplasms (MPNs) in European populations. Whether these germline variations are associated with MPNs in Taiwanese population is obscure. Here we aimed to evaluate the association of five germline variations ( JAK2 46/1 haplotype tagged by rs12343867, JAK2 intron 8 rs12339666, TERT rs2736100, HBS1L - MYB rs9376092 and MECOM rs2201862) and the risk of MPNs in Taiwanese population. A total of 178 MPN patients (109 essential thrombocythemia, 54 polycythemia vera and 15 primary myelofibrosis) were enrolled into this study. The information of 17033 control subjects was obtained from Taiwan Biobank database. The JAK2 46/1 haplotype, JAK2 rs12339666 and TERT rs2736100 were significantly associated with Taiwanese MPNs ( P = 3.6x10 -19 , 1.9x10 -19 and 3.1x10 -6 , respectively), and JAK2 V617F -positive MPNs (n=121) ( P = 5.6x10 -21 , 4.4x10 -21 and 8.6x10 -7 , respectively). In JAK2 V617F -negative cases (n=55), only the JAK2 46/1 haplotype and JAK2 rs12339666 remained statistically significant ( P = 0.009 and 0.007, respectively). When stratified by disease subtypes, the JAK2 46/1 haplotype and JAK2 rs12339666 were significantly associated with all three MPN subtypes, but TERT rs2736100 was only associated with essential thrombocythemia and polycythemia vera. We did not find any association of these five SNPs with CALR mutations in our cohort. Furthermore, the risk alleles of MECOM rs2201862 and HBS1L - MYB rs9376092 were demonstrated to be negatively associated with the risk of developing polycythemia vera. In conclusion, germline variations at JAK2 (both the 46/1 haplotype and rs12339666) and TERT rs2736100 were associated with MPNs in Taiwanese population.
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- 2017
11. Increased B cell activation is present in JAK2V617F-mutated, CALR-mutated and triple-negative essential thrombocythemia
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Ming-Chih Chang, Yuan-Yeh Kuo, Caleb Gon-Shen Chen, Ling Huang, Wei-Ting Wang, Yu-Cheng Chang, Chen-Wei Kao, Ruey-Kuen Hsieh, Huan-Chau Lin, Nai-Wen Su, Yi-Fang Chang, Hung-I Cheng, Yi-Hao Chiang, Ching-Sung Lin, Chun-Chia Cheng, Johnson Lin, Chiao-Yi Chang, and Ken-Hong Lim
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Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lymphocyte Activation ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,CALR ,B-cell activating factor ,Myelofibrosis ,Myeloproliferative neoplasm ,B cell ,Aged ,B-Lymphocytes ,Hematology ,essential thrombocythemia ,biology ,Essential thrombocythemia ,business.industry ,Janus Kinase 2 ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Case-Control Studies ,Mutation ,Immunology ,biology.protein ,Female ,immune ,Calreticulin ,business ,CD80 ,Thrombocythemia, Essential ,Research Paper - Abstract
// Ken-Hong Lim 1,2,3,4 , Caleb Gon-Shen Chen 2,3,4,5 , Yu-Cheng Chang 2,3,4 , Yi-Hao Chiang 2,3 , Chen-Wei Kao 3 , Wei-Ting Wang 3 , Chiao-Yi Chang 3 , Ling Huang 3 , Ching-Sung Lin 3 , Chun-Chia Cheng 3 , Hung-I Cheng 6 , Nai-Wen Su 2,3,4 , Johnson Lin 2 , Yi-Fang Chang 2,3,4 , Ming-Chih Chang 2,3,4 , Ruey-Kuen Hsieh 2,3 , Huan-Chau Lin 2,3 and Yuan-Yeh Kuo 1 1 Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan 2 Department of Internal Medicine, Division of Hematology and Oncology, MacKay Memorial Hospital, Taipei, Taiwan 3 Department of Medical Research, Laboratory of Good Clinical Research Center, MacKay Memorial Hospital, Tamsui District, New Taipei City, Taiwan 4 Department of Medicine, MacKay Medical College, New Taipei City, Taiwan 5 Institute of Molecular and Cellular Biology, National Tsing-Hua University, Hsinchu, Taiwan 6 Department of Internal Medicine, Division of Hematology and Oncology, MacKay Memorial Hospital, Hsinchu, Taiwan Correspondence to: Ken-Hong Lim, email: // Huan-Chau Lin, email: // Yuan-Yeh Kuo, email: // Keywords : B cell, CALR, essential thrombocythemia, immune Received : January 06, 2017 Accepted : February 28, 2017 Published : March 18, 2017 Abstract Essential thrombocythemia (ET) is a BCL-ABL1 -negative myeloproliferative neoplasm. We have reported that increased activated B cells can facilitate platelet production mediated by cytokines regardless JAK2 mutational status in ET. Recently, calreticulin ( CALR ) mutations were discovered in ~30% JAK2 / MPL- unmutated ET and primary myelofibrosis. Here we sought to screen for CALR mutations and to evaluate B cell immune profiles in a cohort of adult Taiwanese ET patients. B cell populations, granulocytes/monocytes membrane-bound B cell-activating factor (mBAFF) levels, B cells toll-like receptor 4 (TLR4) expression and intracellular levels of interleukin (IL)-1β/IL-6 and the expression of CD69, CD80, and CD86 were quantified by flow cytometry. Serum BAFF concentration was measured by ELISA. 48 healthy adults were used for comparison. 19 (35.2%) of 54 ET patients harbored 8 types of CALR exon 9 mutations including 4 (7.4%) patients with concomitant JAK2 V617F mutations. Compared to JAK2 V617F mutation, CALR mutations correlated with younger age at diagnosis ( p =0.04), higher platelet count ( p =0.004), lower hemoglobin level ( p =0.013) and lower leukocyte count ( p =0.013). Multivariate analysis adjusted for age, sex, follow-up period and hematological parameters confirmed that increased activated B cells were universally present in JAK2 -mutated, CALR -mutated and triple-negative ET patients when compared to healthy adults. JAK2 - and CALR -mutated ET have significantly higher fraction of B cells with TLR4 expression when compared to triple-negative ET ( p =0.019 and 0.02, respectively). CALR -mutated ET had significantly higher number of CD69-positive activated B cells when compared to triple-negative ET ( p =0.035). In conclusion, increased B cell activation is present in ET patients across different mutational subgroups.
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- 2017
12. STAT3 induces G9a to exacerbate HER3 expression for the survival of epidermal growth factor receptor-tyrosine kinase inhibitors in lung cancers
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Ya Wen Chiang, Jungshan Chang, Ken-Hong Lim, Chun Chia Cheng, Ai Sheng Ho, Yi Fang Chang, and Zong Lin Sie
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0301 basic medicine ,Male ,Cancer Research ,Lung Neoplasms ,Receptor, ErbB-3 ,Mice, SCID ,STAT3 ,Mice ,0302 clinical medicine ,Cell Movement ,Mice, Inbred NOD ,Histocompatibility Antigens ,Epidermal growth factor receptor ,Gene knockdown ,biology ,Kinase ,Imidazoles ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,ErbB Receptors ,Oncology ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Lung cancer ,Research Article ,STAT3 Transcription Factor ,G9a ,Cell Survival ,EGFR ,lcsh:RC254-282 ,03 medical and health sciences ,Downregulation and upregulation ,HER3 ,Genetics ,medicine ,Animals ,Humans ,Nuclear Factor 90 Proteins ,Protein Kinase Inhibitors ,Benzofurans ,BBI608 ,Cancer ,Histone-Lysine N-Methyltransferase ,medicine.disease ,Xenograft Model Antitumor Assays ,respiratory tract diseases ,MicroRNAs ,030104 developmental biology ,Tumor progression ,A549 Cells ,Drug Resistance, Neoplasm ,biology.protein ,Cancer research ,Naphthoquinones - Abstract
Background HER3 mediates drug resistance against epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers. Previously, we demonstrated that EGFR induces HER3 overexpression, which facilitates the formation of cancer stem-like tumorspheres. However, the cellular mechanism through which EGFR regulates HER3 expression remains unclear. We hypothesized that EGFR downstream of STAT3 participates in HER3 expression because STAT3 contributes to cancer stemness and survival of EGFR-TKI resistant cancers. Methods First, RNAseq was used to uncover potential genes involved in the formation of lung cancer HCC827-derived stem-like tumorspheres. EGFR-positive lung cancer cell lines, including HCC827, A549, and H1975, were individually treated with a panel containing 172 therapeutic agents targeting stem cell-associated genes to search for potential agents that could be applied against EGFR-positive lung cancers. In addition, gene knockdown and RNAseq were used to investigate molecular mechanisms through which STAT3 regulates tumor progression and the survival in lung cancer. Results BBI608, a STAT3 inhibitor, was a potential therapeutic agent that reduced the cell viability of EGFR-positive lung cancer cell lines. Notably, the inhibitory effects of BBI608 were similar with those associated with YM155, an ILF3 inhibitor. Both compounds reduced G9a-mediated HER3 expression. We also demonstrated that STAT3 upregulated G9a to silence miR-145-5p, which exacerbated HER3 expression in this study. Conclusions The present study revealed that BBI608 could eradicate EGFR-positive lung cancers and demonstrated that STAT3 enhanced the expression of HER3 through miR-145-5p repression by G9a, indicating that STAT3 is a reliable therapeutic target against EGFR-TKI-resistant lung cancers.
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- 2019
13. STAT3 Mediated miR-30a-5p Inhibition Enhances Proliferation and Inhibits Apoptosis in Colorectal Cancer Cells
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Ai-Sheng Ho, Chun-Chao Chang, Wen-Chao Chen, Zong-Lin Sie, Chun-Chia Cheng, Hsin-Chi Lin, and Bi-Ling Yang
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0301 basic medicine ,Colorectal cancer ,Apoptosis ,medicine.disease_cause ,lcsh:Chemistry ,STAT3 ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,lcsh:QH301-705.5 ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Spectroscopy ,biology ,miR-30a-5p ,General Medicine ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Colorectal Neoplasms ,HT29 Cells ,STAT3 Transcription Factor ,Cell Survival ,colorectal cancer ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Regorafenib ,microRNA ,medicine ,Humans ,Viability assay ,HSPA5 ,Physical and Theoretical Chemistry ,Molecular Biology ,Cell Proliferation ,Organic Chemistry ,Cancer ,HCT116 Cells ,medicine.disease ,MicroRNAs ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,STAT protein ,biology.protein ,Cancer research ,regorafenib ,Carcinogenesis - Abstract
Signal transducer and activator of transcription 3 (STAT3), a transcriptional factor involved in tumorigenesis and cancer stemness formation, contributes to drug resistance in cancer therapies. STAT3 not only mediates gene transcription but also participates in microRNA suppression. This study identified a STAT3-downstream micro RNA (miRNA) involved in drug resistance against regorafenib in colorectal cancer stem-like tumorspheres. Small RNAseq was used to investigate differential microRNAs in colorectal cancer cell-derived tumorspheres and in a STAT3-knockdown strain. The miRNA-mediated genes were identified by comparing RNAseq data with gene targets predicted using TargetScan. Assays for detecting cell viability and apoptosis were used to validate findings. The formation of colorectal cancer stem-like tumorspheres was inhibited by BBI608, a STAT3 inhibitor, but not by regorafenib. Additional investigations for microRNA expression demonstrated an increase in 10 miRNAs and a decrease in 13 miRNAs in HT29-derived tumorspheres. A comparison of small RNAseq results between tumorspheres and HT29shSTAT3 cells revealed the presence of four STAT3-mediated miRNAs in HT29-derived tumorspheres: hsa-miR-215-5p, hsa-miR-4521, and hsa-miR-215-3p were upregulated, whereas miR-30a-5p was downregulated. Furthermore, hsa-miR-4521 was associated with poor overall survival probability, and miR-30a-5p was associated with better overall survival probability in patients with rectum cancer. Comparisons of RNAseq findings between HCT116- and HT29-derived tumorspheres revealed that HSPA5 were mediated by the STAT3-miR-30a-5p axis, which is overexpressed in colorectal tumorspheres associating to anti-apoptosis. In addition, the transfection of miR-30a-5p and inhibition of HSPA5 by HA15 significantly reduced cell viability and increased apoptosis in HT29 cells. In conclusion, a STAT3-miR-30a-5p-HSPA5 axis was observed against regorafenib-mediated apoptosis in colorectal cancer tumorspheres. The expression of miR-30a-5p was repressed by STAT3, in addition, HSPA5 was identified as the target gene of miR-30a-5p and contributed to both tumorsphere formation and anti-apoptosis.
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- 2020
14. Sulfonamide derivative targeting carbonic anhydrase IX as a nuclear imaging probe for colorectal cancer detectionin vivo
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Shing-Hwa Liu, Cheng Tien Wu, Chun Chia Cheng, Tse Zung Liao, Jungshan Chang, Ai Sheng Ho, Tsai Yueh Luo, Siao Syun Guan, and Chia-Chi Wang
- Subjects
Diagnostic Imaging ,Male ,Pathology ,medicine.medical_specialty ,Colorectal cancer ,radioisotope-labeled ,colorectal cancer ,carbonic anhydrase IX ,Mice ,Antigens, Neoplasm ,In vivo ,Cell Line, Tumor ,sulfonamide ,medicine ,Animals ,Humans ,Viability assay ,Radionuclide Imaging ,Carbonic Anhydrases ,Mice, Inbred BALB C ,Sulfonamides ,business.industry ,Sulfonamide (medicine) ,Carbonic Anhydrase IX ,Hypoxia (medical) ,medicine.disease ,Cell Hypoxia ,In vitro ,Oncology ,Cancer research ,Heterografts ,Biomarker (medicine) ,medicine.symptom ,Colorectal Neoplasms ,business ,Research Paper ,medicine.drug - Abstract
Hypoxic microenvironment is a common situation in solid tumors. Carbonic anhydrase IX (CA9) is one of the reliable cellular biomarkers of hypoxia. The role of CA9 in colorectal cancer (CRC) remains to be clarified. CA9 inhibitor such as sulfonamides is known to block CA9 activation and reduce tumor growth consequently. Here, we aimed to investigate the CA9 expression in serum and tumor from different stages of CRC patients and utilize sulfonamide derivative with indium-111 labeling as a probe for CRC nuclear imaging detection in vivo. The serum CA9 was correlated with the tumor CA9 levels in different stages of CRC patients. Hypoxia increased cell viability and CA9 expression in colorectal cancer HCT-15 cells. Sulfonamide derivative 5-(2-aminoethyl)thiophene-2-sulfonamide (ATS) could bind with CA9 in vitro under hypoxia. Moreover, tumor tissues in HCT-15-induced xenograft mice possessed higher hypoxic fluorescence signal as compared with other organs. We also found that the radioisotope signal of indium-111 labeled ATS, which was utilized for CRC detection in HCT-15-induced xenograft mice, was markedly enhanced in tumors as compared with non-ATS control. Taken together, these findings suggest that CA9 is a potential hypoxic CRC biomarker and measurement of serum CA9 can be as a potential tool for diagnosing CA9 expressions in CRC clinical practice. The radioisotope-labeled sulfonamide derivative (ATS) may be useful to apply in CRC patients for nuclear medicine imaging.
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- 2015
15. Epidermal growth factor induces STAT1 expression to exacerbate the IFNr-mediated PD-L1 axis in epidermal growth factor receptor-positive cancers
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Ai Sheng Ho, Yu-Cheng Chang, Ying Wen Su, Jungshan Chang, Yi Fang Chang, Chun Chia Cheng, Cheng Liang Peng, Huan Chau Lin, Ya Wen Chiang, Hsin Chi Lin, Caleb Gon-Shen Chen, Ken-Hong Lim, Kaun Jer Tsai, and Ling Huang
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Afatinib ,B7-H1 Antigen ,Immunophenotyping ,03 medical and health sciences ,Interferon-gamma ,Mice ,0302 clinical medicine ,Cancer stem cell ,Epidermal growth factor ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Epidermal growth factor receptor ,Lung cancer ,Molecular Biology ,Protein Kinase Inhibitors ,Gene knockdown ,biology ,Epidermal Growth Factor ,medicine.disease ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,STAT1 Transcription Factor ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,CD8 ,Biomarkers ,medicine.drug - Abstract
The epidermal growth factor (EGF) receptor (EGFR) overexpressed in many cancers, including lung and head and neck cancers, and is involved in cancer cell progression and survival. PD-L1, increases in tumor cells to evade and inhibit CD8+ T cells, is a clinical immunotherapeutic target. This study investigated the molecular mechanism of EGF on regulating PD-L1 in EGFR-positive cancers and determined potential agents to reduce PD-L1 expression. RNA sequencing (RNAseq) and bioinformatics analysis were performed to determine potential driver genes that regulate PD-L1 in tumor cells-derived tumorspheres which mimicking cancer stem cells. Then, the specific inhibitors targeting EGFR were applied to reduce the expression of PD-L1 in vitro and in vivo. We validated that EGF could induce PD-L1 expression in the selected EGFR-positive cancers. RNAseq results revealed that STAT1 increased as a driver gene in KOSC-3-derived tumorspheres; these data were analyzed using PANTHER followed by NetworkAnalyst. The blockade of EGFR by afatinib resulted in decreased STAT1 and IRF-1 levels, both are transcriptional factors of PD-L1, and disabled the IFNr-STAT1-mediated PD-L1 axis in vitro and in vivo. Moreover, STAT1 knockdown significantly reduced EGF-mediated PD-L1 expression, and ruxolitinib, a JAK1/JAK2 inhibitor, significantly inhibited STAT1 phosphorylation to reduce the IFNr-mediated PD-L1 axis. These results indicate that EGF exacerbates PD-L1 by increasing the protein levels of STAT1 to enforce the IFNr-JAK1/2-mediated signaling axis in selected EGFR-positive cancers. The inhibition of EGFR by afatinib significantly reduced PD-L1 and may be a potential strategy for enhancing immunotherapeutic efficacy.
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- 2018
16. Pravastatin inhibits tumor growth through elevating the levels of apolipoprotein A1
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Chun-Chia Cheng, Ai-Sheng Ho, Jungshan Chang, Hua-Ching Lin, Tsai-Yueh Luo, and Chun Yeh
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0301 basic medicine ,Colorectal cancer ,Inflammation ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,Medicine, General & Internal ,0302 clinical medicine ,polycyclic compounds ,medicine ,Doxorubicin ,Pravastatin ,biology ,Cholesterol ,business.industry ,nutritional and metabolic diseases ,Cancer ,General Medicine ,medicine.disease ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Apolipoprotein A1 ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Gastric cancer ,business ,medicine.drug ,Lipoprotein - Abstract
Summary Background Statins are a class of drugs used to lower cholesterol levels, accompanying increased high-density lipoprotein (HDL) levels. Previous studies have suggested that statins can inhibit inflammation, and also reduce tumor proliferation. We therefore hypothesized that pravastatin, a member of the statins, mediating the inhibitory functions in tumor growth may be associated with the upregulated HDL constituent, apolipoprotein A1 (ApoA1). Methods Pravastatin-induced inhibition in tumor proliferation in vitro and in xenografts was investigated. Reduced ApoA1 expressions were detected in the tumor regions in specimens from tumor patients as well in xenografts using Western Blotting. Moreover, ApoA1 was administered to inhibit tumor proliferation, and pravastatin was given to enhance the chemotherapeutic efficacy of doxorubicin (DOX). Results We found a significant statistical reduction of ApoA1 in the tumor regions of specimens from gastric cancer and colorectal cancer patients. MKN45 cells proliferation was inhibited by 18% under the growing medium containing pravastatin. ApoA1 levels were elevated in liver Clone 9 cells administered pravastatin, but not in MKN45 cells. In vitro studies revealed that ApoA1 can reduce MKN45 tumor proliferation. Moreover, the tumor volume was significantly reduced in in vivo xenografts after the administration of pravastatin. Combined treatments of pravastatin with DOX significantly minimized the size of tumors, leading to a better therapeutic efficacy. Conclusion This study demonstrated that pravastatin elevated ApoA1, an HDL major constituent with anti-inflammatory characteristics, which displayed strong adversary associations with tumor developments and growth. Increasing the amounts of ApoA1 by pravastatin coupled with DOX may improve the therapeutic efficacy for cancer treatment.
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- 2015
17. Trends of Gold Nanoparticle-based Drug Delivery System in Cancer Therapy
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Tzuchun Kan, Teh-Hua Tsai, Jungshan Chang, Giimel Ajnai, Chun Chia Cheng, and Amy Chiu
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business.industry ,Nanoparticle ,Cancer ,General Medicine ,Pharmacology ,medicine.disease ,Review article ,Colloidal gold ,Drug delivery ,medicine ,Nanomedicine ,Drug carrier ,Cytotoxicity ,business - Abstract
Following surgical removal of malignant tumors, chemotherapeutic intervention usually is subsequently applied in patients with advanced stages of cancer. Most chemotherapeutic drugs are intravenously injected into patients, leading to systemic cytotoxicity in organs and tissues, including healthy tissue and tumors. Currently, it has been demonstrated that gold nanoparticles can easily penetrate blood vessels and tissue barriers into tumor foci, which indicates gold nanoparticles as a more effective drug carrier with great merits in reducing cytotoxicity and economic burden in patients. Moreover, gold nanoparticles display several unique characterizations with multiple functions in therapeutics, imaging, and surface modification, suggesting gold nanoparticles may become effective antitumor drug carriers. In this review article, we discuss the limitations and applications of gold nanoparticles in surface modification, targeting strategy, and safety considerations.
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- 2014
18. Targeted next-generation sequencing identified novel mutations in triple-negative myeloproliferative neoplasms
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Yi-Hao Chiang, Ruey-Kuen Hsieh, Ken-Hong Lim, Yuan-Yeh Kuo, Huan-Chau Lin, Caleb Gon-Shen Chen, Ming-Chih Chang, Johnson Lin, Shu-Jen Chen, Yu-Cheng Chang, Chun-Chia Cheng, Wei-Ting Wang, Yi-Fang Chang, and Ling Huang
- Subjects
Adult ,Male ,0301 basic medicine ,Cancer Research ,Adolescent ,DNA Mutational Analysis ,Biology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Myeloproliferative Disorders ,medicine ,Humans ,Myelofibrosis ,Allele frequency ,Germ-Line Mutation ,Myeloproliferative neoplasm ,Aged ,Aged, 80 and over ,Genetics ,Mutation ,Essential thrombocythemia ,Cancer ,DNA, Neoplasm ,Sequence Analysis, DNA ,Hematology ,General Medicine ,Janus Kinase 2 ,Middle Aged ,medicine.disease ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Female ,Calreticulin ,Receptors, Thrombopoietin - Abstract
Mutations in JAK2, MPL and CALR genes have been identified in the majority of myeloproliferative neoplasm (MPN) patients, and patients negative for these three mutations are the so-called triple-negative (TN) MPN. In this study, we examined the mutational profiles of 16 triple-negative MPN patients including 7 essential thrombocythemia (ET), 1 primary myelofibrosis and 8 polycythemia vera (PV). Targeted next-generation sequencing was performed using the ACTOnco Comprehensive Cancer Panel (Ion AmpliSeq Comprehensive Cancer Panel, Life Technologies) to target all coding exons of 409 cancer-related genes. Overall, 30 nonsynonymous somatic mutations were detected in 12 (75%) patients with a range of 1-5 mutations per sample. Notably, one ET patient was found to have JAK2V617F and KITP551L mutations at very low allele frequency. One MPLP70L and 1 MPLM602T mutations were identified each in 1 ET and 1 PV, respectively. Other recurrent mutations were also identified including KMT2C, KMT2D, IRS2, SYNE1, PDE4DIP, SETD2, ATM, TNFAIP3 and CCND2. In addition, germline mutations were also found in some cancer-related genes. Copy number changes were rare in this cohort of TN MPNs. In conclusion, both somatic and germline mutations can be detected in TN MPN patients.
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- 2017
19. Afatinib and its encapsulated polymeric micelles inhibits HER2-overexpressed colorectal tumor cell growthin vitroandin vivo
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Cheng Tien Wu, Chun Chia Cheng, Shing-Hwa Liu, Ai Sheng Ho, Jungshan Chang, Tsai Yueh Luo, Siao Syun Guan, and Chia-Chi Wang
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Adult ,Male ,Oncology ,medicine.medical_specialty ,micelles ,Cell Survival ,Polymers ,Receptor, ErbB-2 ,Colorectal cancer ,Drug Compounding ,Afatinib ,Immunoblotting ,afatinib ,Mice, Nude ,colorectal cancer ,Apoptosis ,In vivo ,HER2 ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Humans ,skin and connective tissue diseases ,neoplasms ,Aged ,Cell Proliferation ,Mice, Inbred BALB C ,business.industry ,Cell growth ,Therapeutic effect ,Cancer ,Hep G2 Cells ,Middle Aged ,Hepatology ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,In vitro ,Tumor Burden ,MCF-7 Cells ,Quinazolines ,Female ,Colorectal Neoplasms ,business ,Research Paper ,medicine.drug - Abstract
// Siao-Syun Guan 1,2 , Jungshan Chang 3 , Chun-Chia Cheng 2,3 , Tsai-Yueh Luo 2 , Ai-Sheng Ho 4 , Chia-Chi Wang 5 , Cheng-Tien Wu 1 and Shing-Hwa Liu 1,6,7 1 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 2 Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan 3 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan 4 Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, Taiwan 5 Division of Hepatology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan 6 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan 7 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan Correspondence: Shing-Hwa Liu, email: // Keywords : colorectal cancer / HER2 / afatinib / micelles Received : March 31, 2014 Accepted : May 30, 2014 Published : June 1, 2014 Abstract Colorectal cancer (CRC) is known as a common malignant neoplasm worldwide. The role of EGFR/HER2 in CRC is unclear. Afatinib is an irreversible EGFR/HER2 inhibitor. There were few studies of afatinib on CRC. Here, we investigated the protein levels/expressions of HER2 in sera and tumors from CRC patients and the therapeutic effect of afatinib on HER2-overexpressed CRC in vitro and in vivo . The increased HER2 levels were detected in the collected sera and tumors of patients with CRC. The serological HER2 levels were correlated with the tumor HER2 expressions in patients. Afatinib also inhibited the HER2-positive tumor cell growth and caused apoptosis in HER2-overexpressed human colorectal cancer HCT-15 cells but not in low HER2 expressed human gastric cancer MKN45 cells. In vivo study showed that afatinib reduced tumor growth in HER2-overexpressed xenografts. Moreover, afatinib-encapsulated micelles displayed higher cytotoxic activity in HCT-15 cells and were more effective for tumor growth suppression in HCT-15-induced tumor xenografts than afatinib performance alone. Taken together, these findings suggest that higher serum HER2 levels reflect the higher HER2 contents in tumors of CRC patients, and the improved afatinib-encapsulated micelles possess high therapeutic efficacy in HER2-overexpressed CRC in vitro and in vivo .
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- 2014
20. Abstract 3028: STAT3 represses miR-145-5p to exacerbate HER3 expression for surviving EGFR-TKIs in lung cancers
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Ken-Hong Lim, Ya-Wen Chiang, Jungshan Chang, Chun-Chia Cheng, Ai-Sheng Ho, and Yi-Fang Chang
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Cancer Research ,Gene knockdown ,biology ,business.industry ,Cancer ,medicine.disease ,respiratory tract diseases ,Oncology ,Downregulation and upregulation ,Tumor progression ,Cancer research ,biology.protein ,medicine ,Epidermal growth factor receptor ,STAT3 ,Lung cancer ,business ,Tyrosine kinase - Abstract
HER3 exerts resistance against epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers. Previously, we have demonstrated that EGFR induces HER3 overexpression and that contributes to the formation of cancer stem-like tumorspheres. However, the cellular mechanism of EGFR in regulating HER3 expression was obscure. We hypothesized that EGFR-downstream STAT3 participates in HER3 expression since STAT3 contributes to cancer stemness and surviving EGFR-TKIs. First, RNAseq was used to uncover the potential genes involving in formation of lung cancer HCC827-derived stem-like tumorspheres. EGFR-positive lung cancer cell lines (HCC827, A549, H1975) were individually treated with a panel containing 172 compounds which targeting to stem cell-associated genes in order to searching potential agents against EGFR-positive lung cancers. In addition, gene knockdown and RNAseq were used for investigating the molecular mechanism of STAT3 on regulating tumor progression and survival of lung cancers. We found that BBI608, a STAT3 inhibitor, was a potential therapeutic agent specifically reducing the cell viability of EGFR-positive lung cancers. Interestingly, the inhibitory effects caused by BBI608 were similar with that derived from YM155, an ILF3 inhibitor, both compounds reduced G9a-mediated HER3 expression. We, furthermore, demonstrated that STAT3 upregulated G9a to silence miR-145-5p for exacerbating HER3 expression in this study. In conclusion, this study figured out the potential cellular function of STAT3 in EGFR-positive lung cancers. We also evaluated that BBI608 was potential to eradicate EGFR-positive lung cancers and demonstrated that STAT3 regulated expression of HER3, indicating that STAT3 was a reliable therapeutic target against EGFR-TKI-resistant lung cancers. Note: This abstract was not presented at the meeting. Citation Format: Chun-Chia Cheng, Ya-Wen Chiang, Ken-Hong Lim, Jungshan Chang, Ai-Sheng Ho, Yi-Fang Chang. STAT3 represses miR-145-5p to exacerbate HER3 expression for surviving EGFR-TKIs in lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3028.
- Published
- 2019
21. Sa1696 – Stat3-Mediated Gene and Mirna Expression Profiling Analysis in Colorectal Cancer Cells-Derived Cancer Stem-Like Tumorspheres
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Bi-Ling Yang, Ai-Sheng Ho, and Chun-Chia Cheng
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Hepatology ,biology ,Mirna expression ,Colorectal cancer ,Gastroenterology ,biology.protein ,Cancer research ,medicine ,Profiling (information science) ,STAT3 ,medicine.disease ,Gene - Published
- 2019
22. Distinct Microrna Profiles in Patients with Essential Thrombocythemia: Clinical and Prognostic Correlation
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Ling Huang, Nai-Wen Su, Ken-Hong Lim, Yi-Hao Chiang, Shih-Ting Kang, Tiffany Wang, Ming-Chih Chang, Yu-Cheng Chang, Yi-Fang Chang, Johnson Lin, Chun-Chia Cheng, Wei-Ming Chen, Jian-Yi Lin, Huan-Chau Lin, Caleb Gon-Shen Chen, Ruey-Kuen Hsieh, and Yu Shan Huang
- Subjects
Sanger sequencing ,Oncology ,Hippo signaling pathway ,medicine.medical_specialty ,Thrombocytosis ,business.industry ,Essential thrombocythemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,symbols.namesake ,Internal medicine ,microRNA ,symbols ,Medicine ,KEGG ,business ,Myelofibrosis ,Myeloproliferative neoplasm - Abstract
Background: Essential thrombocythemia (ET) is a BCL-ABL1-negative myeloproliferative neoplasm characterized by increased number of mature megakaryocytes in the bone marrow and sustained thrombocytosis in the peripheral blood. ET is associated with an increased risk of hemorrhagic and thrombotic complications and leukemic transformation. In addition to somatic mutations, microRNA (miRNA) deregulation has been proposed to play roles in the molecular pathogenesis and disease phenotype in ET patients. The aims of this study were to investigate the plasma miRNA profiles in ET patients with those obtained from healthy adults (HA) and its correlation with clinical and prognostic features. Methods: ET patients seen at the MacKay Memorial Hospital were enrolled into this study. The clinical and laboratory characteristics at the time of diagnosis or referral were determined retrospectively by chart review. Total plasma miRNA was derived from bone marrow or peripheral blood in patients or HA. Mutational status of JAK2V617F,CALR and MPL were detected by Sanger sequencing and/or allele-specific PCR. Plasma miRNA profiling was carried out on PanelChip™ Analysis System (Quark Biosciences, Taiwan) using a customized miRNA panel including 165 miRNAs called mirSCAN™ PanCancer Chips 1 & 2. KEGG pathways that miRNAs were associated with were analyzed using DIANA TOOLS - mirPath v.3. Differentially expressed miRNAs were identified by student t-test (P < 0.05) and significantly affected miRNAs in ET were identified by a change in expression of two-fold or more compared to the expression in HA. Statistical analysis was performed using SPSS. Results: A total of 53 ET patients (median age at diagnosis 59 years; 60.4% females) were enrolled. Frequency of the 3 driver mutations was 64% for JAK2V617F, 15% CALR, 4% JAK2V617F and CALR co-mutations, and none for MPL. 17% of patients were classified as triple-negative. A total of 40 differentially expressed miRNAs were identified (Figure left axis) including 4 miRNAs (hsa-miR-940, hsa-miR-411-5p, hsa-miR-596 and hsa-miR-376c-3p) with higher expression levels. The putative target genes of these 40 differentially expressed miRNAs were enriched in signaling pathway including TGF-beta signaling pathway (p-value = 1.86E-12), Hippo signaling pathway (p-value = 1.84E-07), MAPK signaling pathway (p-value = 0.03), and FoxO signaling pathway (p-value < 0.001). According to the expression levels of these 40 miRNAs, samples were grouped into two clusters, i.e. low expression group and high expression group. ET patients with JAK2V617F were significantly associated with high expression of 40 miRNAs (n = 31 of 34, 91%) when compared with triple-negative ET patients (n = 5 of 9, 56%) (p = 0.03). ET patients with low expression of 40 miRNAs were significantly associated with acute leukemia transformation (n = 2 of 11, 18%) when compared with high expression group (n = 0 of 42, 0%) (p = 0.04). However, the expression levels of 40 miRNAs were not statistically correlated with other clinical features including hemogram, secondary solid cancer, myelofibrosis transformation, or thrombotic/hemorrhagic events. Conclusions: In this cohort of ET patients, distinct plasma miRNA profiles correlated with JAK2V617F mutation and leukemic transformation. Larger cohort is warranted to validate our findings. Figure Figure. Disclosures Chen: Quark Biosciences, Inc.: Employment. Kang:Quark Biosciences, Inc.: Employment. Huang:Quark Biosciences, Inc.: Employment. Lin:Quark Biosciences, Inc.: Employment. Wang:Quark Biosciences, Inc.: Employment.
- Published
- 2018
23. Novel targeted nuclear imaging agent for gastric cancer diagnosis: glucose-regulated protein 78 binding peptide-guided 111In-labeled polymeric micelles
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Tsai Yueh Luo, Jungshan Chang, Cheng Liang Peng, Chun Chia Cheng, Ai Sheng Ho, Chiung Fang Huang, Ling-Yun Chen, Chun Chao Chang, and Fu Der Mai
- Subjects
Materials science ,micelles ,Biophysics ,Pharmaceutical Science ,Mice, Nude ,Bioengineering ,Conjugated system ,Single-photon emission computed tomography ,Micelle ,Biomaterials ,chemistry.chemical_compound ,Mice ,International Journal of Nanomedicine ,Stomach Neoplasms ,Cell Line, Tumor ,Drug Discovery ,medicine ,Biomarkers, Tumor ,glucose-regulated protein 78 ,Animals ,Humans ,Particle Size ,Radionuclide Imaging ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Original Research ,nuclear imaging ,Drug Carriers ,medicine.diagnostic_test ,gastric cancer ,Organic Chemistry ,Indium Radioisotopes ,Cancer ,General Medicine ,medicine.disease ,Thin-layer chromatography ,Molecular Imaging ,chemistry ,Biochemistry ,biomarker ,Heterografts ,Molecular imaging ,Radiopharmaceuticals ,Drug carrier ,Peptides ,Ethylene glycol - Abstract
Chun-Chia Cheng,1,2,* Chiung-Fang Huang,3,4,* Ai-Sheng Ho,5 Cheng-Liang Peng,6 Chun-Chao Chang,7,8 Fu-Der Mai,1,9 Ling-Yun Chen,10 Tsai-Yueh Luo,2 Jungshan Chang1,11,121Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, 2Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, 3School of Dental Technology, Taipei Medical University, Taipei, 4Division of Family and Operative Dentistry, Department of Dentistry, Taipei Medical University Hospital, Taipei, 5Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, 6Institute of Biomedical Engineering, National Taiwan University, Taipei, 7Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, 8Department of Internal Medicine, Taipei Medical University, Taipei, 9Department of Biochemistry, Taipei Medical University, Taipei, 10Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, 11Neuroscience Research Center, Taipei Medical University Hospital, Taipei, 12Research Center for Biomedical Implants and Microsurgery Devices, Taipei Medical University, Taipei, Taiwan*These authors contributed equally to this workAbstract: Increased expression of cellular membrane bound glucose-regulated protein 78 (GRP78) is considered to be one of the biomarkers for gastric cancers. Therefore, peptides or molecules with specific recognition to GRP78 can act as a guiding probe to direct conjugated imaging agents to localized cancers. Based on this rationale, GRP78-guided polymeric micelles were designed and manufactured for nuclear imaging detection of tumors. Thiolated GRP78 binding peptide (GRP78BP) was first labeled with maleimide-terminated poly(ethylene glycol)–poly(ε-caprolactone) and then mixed with diethylenetriaminepentaacetic acid (DTPA)-linked poly(ethylene glycol)–poly(ε-caprolactone) to form DTPA/GRP78BP-conjugated micelles. The coupling efficiency of micelles with radioisotope indium-111 (111In) was measured and analyzed by instant thin layer chromatography. The coupling efficiency of DTPA-conjugated micelles and DTPA/GRP78BP-conjugated micelles with 111In was 85% and 93%, respectively. For characterization and trace imaging, the radioisotope 111In-targeting tumors were detected and imaged in a xenograft murine model using nano single photon emission computed tomography/computed tomography. The results revealed that the radioactive intensity measured in the animals administered with GRP78BP-guided 111In-labeled micelles was statistically higher than that in animals administered with 111In-labeled micelles, demonstrating that GRP78BP more than doubled the accumulation of micelles to the tumor tissue (P < 0.05). The results indicate that the gastric cancer biomarker GRP78 is a probing target in the application of nuclear imaging for tumor diagnosis. This novel GRP78BP-guided micelle agent may be applied in clinical practice to complement the histological diagnosis.Keywords: biomarker, glucose-regulated protein 78, nuclear imaging, gastric cancer, micelles
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- 2013
24. Targeting to overexpressed glucose-regulated protein 78 in gastric cancer discovered by 2D DIGE improves the diagnostic and therapeutic efficacy of micelles-mediated system
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Cheng Liang Peng, Ling-Yun Chen, Wen Ming Wang, Mei Hsiu Liao, Norman Lu, Chun Chia Cheng, Fu Der Mai, Chun Chao Chang, and Jungshan Chang
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Glucose-regulated protein ,Polyesters ,Blotting, Western ,Molecular Sequence Data ,Ligands ,Bioinformatics ,Biochemistry ,Polyethylene Glycols ,Two-Dimensional Difference Gel Electrophoresis ,Mice ,Stomach Neoplasms ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Endoplasmic Reticulum Chaperone BiP ,Molecular Biology ,Heat-Shock Proteins ,Micelles ,biology ,Reproducibility of Results ,Cancer ,medicine.disease ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,In vitro ,Blot ,Treatment Outcome ,Targeted drug delivery ,Doxorubicin ,Cell culture ,Cancer research ,biology.protein ,Biomarker (medicine) - Abstract
The survivals of gastric cancer (GC) patients are associated with early diagnosis and effective treatments. Therefore, it is urgent for the discovery of early GC biomarkers and tumor-targeting therapeutics. The aim of this study was to uncover putative tissue biomarkers of GC using 2D DIGE and then apply one of these specific markers in GC treatment. We found three putative biomarkers of GC with significant differences in expression level compared to adjacent normal tissue, including glucose-regulated protein 78 (GRP78) and glutathione s-transferase pi (GSTpi) with increased expression level, and alpha-1 antitrypsin (A1AT) with reduced expression level. The overexpressed GRP78 was used as a targeted protein for guiding the drugs to tumor cells, leading to more effective treatment for GC xenografts. Our results demonstrated that the designated GRP78-binding peptide based on the sequence, WIFPWIQL, was selectively prone to recognize and bind to GC MKN45 cells in vitro, and also improve the delivery efficiency of polymeric micelles-encapsulated drugs into tumor cells and displayed better therapeutic outcome in experimental animals. This strategy of GRP78-mediated drug targeting system may bring chemotherapeutic drugs with more precise targeting to tumor cells, leading to minimize side effects on patients after chemotherapy.
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- 2012
25. Metastasis of Breast Cancer to the Sphenoid Sinus Presenting as Tolosa-Hunt Syndrome
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Chih Jaan Tai, Ming Hsui Tsai, Chun Chia Cheng, Guan Chin Tseng, Yung An Tsou, and Meng-Hung Lin
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Medicine(all) ,Pathology ,medicine.medical_specialty ,Sphenoid metastasis ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,General Medicine ,medicine.disease ,Metastasis ,medicine.anatomical_structure ,Breast cancer ,Biopsy ,otorhinolaryngologic diseases ,Medicine ,Radiology ,Invasive Ductal Breast Carcinoma ,business ,Right sphenoid sinus ,Sinus (anatomy) ,Tolosa–Hunt syndrome ,Tolosa-Hunt syndrome - Abstract
Breast cancer with sphenoid sinus metastasis has rarely been reported. A 57-year-old woman presented with Tolosa-Hunt syndrome 1 year after undergoing surgery and chemoradiation therapy for ductal breast cancer. The diagnosis of Tolosa-Hunt syndrome was based on a computed tomography scan and granulomatous pathologic findings from the ethmoid sinuses. Magnetic resonance images revealed an enhanced soft tissue mass mainly in the right sphenoid sinus; the second sinoscopic biopsy revealed metastatic invasive ductal breast carcinoma with intact surface epithelium. The patient died 20 days after the second biopsy. In this report, we discuss the possible metastatic pathway and choice of imaging modalities for the diagnosis of this rare metastatic sphenoid sinus cancer.
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- 2010
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26. Abstract 3060: EGFR-mediated interleukin enhancer-binding factor 3 contributes to formation and survival of cancer stem-like tumorspheres through regulating HER3/ERBB3 expression as a therapeutic target against EGFR-positive non-small cell lung cancer
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Ken-Hong Lim, Caleb Gon-Shen Chen, Kuei-Fang Chou, Ying-Wen Su, Jungshan Chang, Cheng-Wen Wu, Yu-Cheng Chang, Yi-Fang Chang, Ai-Sheng Ho, Nai-Wen Su, Chun-Chia Cheng, Huan-Chau Lin, and Cheng-Liang Peng
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Cancer Research ,Gene knockdown ,biology ,Cell growth ,Afatinib ,Cancer ,medicine.disease ,Oncology ,Cancer stem cell ,Cancer cell ,medicine ,Cancer research ,biology.protein ,ERBB3 ,Epidermal growth factor receptor ,medicine.drug - Abstract
Objectives: YM155, an inhibitor of interleukin enhancer-binding factor 3 (ILF3), significantly suppresses cancer stemness property, implying that ILF3 contributes to cell survival of cancer stem cells. However, the molecular function of ILF3 inhibiting cancer stemness remain unclear. This study aimed to uncover the potential function of ILF3 involving in cell survival of epidermal growth factor receptor (EGFR)-positive lung stem-like cancer, and investigate the potential role to improve the efficacy of anti-EGFR therapeutics. Materials and Methods: The regulated association of EGFR and ILF3 was investigated at first. ILF3 was knockdowned and RNAseq was utilized to search for the putative genes regulated by ILF3. Meanwhile, HCC827- and A549-derived cancer stem-like cells were used to investigate the role of ILF3 in the formation of cancer stem-like tumorspheres. Results: We found that EGFR induced ILF3 expression, and YM155 reduced EGFR expression. The knockdown of ILF3 reduced not only EGFR expression in mRNA and protein levels, but also cell proliferation in vitro and in vivo, demonstrating that ILF3 was an oncoprotein contributing to cancer cell survival. Moreover, the knockdown and inhibition of ILF3 by shRNA and YM155, respectively, reduced the formation and survival of HCC827- and A549-derived tumorspheres through inhibiting HER3/ERBB3 expression, and synergized the therapeutic efficacy of afatinib, a tyrosine kinase inhibitor, against EGFR-positive A549 lung cells. Conclusion: This study demonstrated that ILF3 played an oncogenic role maintaining the EGFR-mediated cellular pathway as a therapeutic target to improve the therapeutic efficacy of afatinib. Therefore, we suggested that YM155, an ILF3 inhibitor, was potential for utilization in cancer therapy against the EGFR-positive cancers. Citation Format: Chun-Chia Cheng, Kuei-Fang Chou, Cheng-Wen Wu, Nai-Wen Su, Cheng-Liang Peng, Ying-Wen Su, Jungshan Chang, Ai-Sheng Ho, Huan-Chau Lin, Caleb Gon-Shen Chen, Yu-Cheng Chang, Ken-Hong Lim, Yi-Fang Chang. EGFR-mediated interleukin enhancer-binding factor 3 contributes to formation and survival of cancer stem-like tumorspheres through regulating HER3/ERBB3 expression as a therapeutic target against EGFR-positive non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3060.
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- 2018
27. YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells
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Cheng-Wen Wu, Ai Sheng Ho, Huan Chau Lin, Yu-Cheng Chang, Chun Chao Chang, Yi Fang Chang, Ken-Hong Lim, Chun Chia Cheng, Stanley Ching-Cheng Huang, Jungshan Chang, and Ling Huang
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0301 basic medicine ,Lung Neoplasms ,Drug Evaluation, Preclinical ,Cancer Treatment ,Gene Expression ,lcsh:Medicine ,Biochemistry ,Lung and Intrathoracic Tumors ,0302 clinical medicine ,Histocompatibility Antigens ,Medicine and Health Sciences ,Growth factor receptor inhibitor ,Epidermal growth factor receptor ,Phosphorylation ,Post-Translational Modification ,lcsh:Science ,DNA methylation ,Multidisciplinary ,biology ,Chemistry ,Autophosphorylation ,Imidazoles ,Chemical Reactions ,Chemical Synthesis ,Chromatin ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,Nucleic acids ,Oncology ,030220 oncology & carcinogenesis ,Physical Sciences ,Epigenetics ,Reductive Methylation ,DNA modification ,Chromatin modification ,Research Article ,Chromosome biology ,Homeobox protein NANOG ,Cell biology ,Antineoplastic Agents ,Afatinib ,Research and Analysis Methods ,Methylation ,03 medical and health sciences ,Cancer stem cell ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,RNA, Messenger ,Lung cancer ,A549 cell ,lcsh:R ,Cancers and Neoplasms ,Biology and Life Sciences ,Proteins ,Cancer ,Histone-Lysine N-Methyltransferase ,DNA ,medicine.disease ,030104 developmental biology ,Quinazolines ,Cancer research ,biology.protein ,lcsh:Q ,Secondary Lung Tumors ,Octamer Transcription Factor-3 ,Naphthoquinones - Abstract
Cancer stem cell survival is the leading factor for tumor recurrence after tumor-suppressive treatments. Therefore, specific and efficient inhibitors of cancer stemness must be discovered for reducing tumor recurrence. YM155 has been indicated to significantly reduce stemness-derived tumorsphere formation. However, the pharmaceutical mechanism of YM155 against cancer stemness is unclear. This study investigated the potential mechanism of YM155 against cancer stemness in lung cancer. Tumorspheres derived from epidermal growth factor receptor (EGFR)-mutant HCC827 and EGFR wild-type A549 cells expressing higher cancer stemness markers (CD133, Oct4, and Nanog) were used as cancer stemness models. We observed that EGFR autophosphorylation (Y1068) was higher in HCC827- and A549-derived tumorspheres than in parental cells; this autophosphorylation induced tumorsphere formation by activating G9a-mediated stemness. Notably, YM155 inhibited tumorsphere formation by blocking the autophosphorylation of EGFR and the EGFR-G9a-mediated stemness pathway. The chemical and genetic inhibition of EGFR and G9a revealed the significant role of the EGFR-G9a pathway in maintaining the cancer stemness property. In conclusion, this study not only revealed that EGFR could trigger tumorsphere formation by elevating G9a-mediated stemness but also demonstrated that YM155 could inhibit this formation by simultaneously blocking EGFR autophosphorylation and G9a activity, thus acting as a potent agent against lung cancer stemness.
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- 2017
28. Abstract 934: EGFR induces ILF3 and G9a expressions to maintain Oct4-mediated stemness property in lung cancer
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Cheng-Wen Wu, Chun-Chao Chang, Huan-Chau Lin, Ai-Sheng Ho, Chun-Chia Cheng, Jungshan Chang, Ken-Hong Lim, and Yi-Fang Chang
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Homeobox protein NANOG ,Cancer Research ,Afatinib ,Cell ,Cancer ,Biology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Cancer stem cell ,Tumor progression ,030220 oncology & carcinogenesis ,Immunology ,medicine ,Cancer research ,biology.protein ,Epidermal growth factor receptor ,Lung cancer ,medicine.drug - Abstract
Cancer stem cells survive and lead to tumor recurrence in tumor therapeutic treatments. Lung cancer cells highly express epidermal growth factor receptor (EGFR), which is critical for tumor progression. We hypothesized that EGFR may play a pivotal role in the induction of cancer stemness cells (CSCs). The aim of this study attempted to investigate the molecular mechanism of EGFR-mediated cancer stemness, and to discover the potent therapeutic agents. A high expression level of cancer stemness markers, ALDH1, CD133, Oct4, and Nanog was observed in tumorspheres derived from HCC827. External EGF further elevated the expression of Oct4 in HCC827 cells. Moreover, chemical inhibition and genetic knockdown of EGFR reduced the Oct4 expression and also tumorsphere formation. We found that inhibitors targeting to EGFR (afatinib), ILF3 (YM155), and G9a (UNC0642) are potential to reduce the formations of tumorspheres. The results revealed that EGFR triggered the formation of tumorspheres through elevating the activations of G9a-mediated stemness genes. In addition, YM155 effectively inhibited tumor growth and formation of tumorspheres as an anti-lung cancer agent blocking the EGFR-G9a cell initiating program pathway. This study demonstrated that EGFR participated in maintain of cancer stemness property through expressing ILF3 and G9a expressions. YM155 inhibited the EGFR-G9a stemness pathway, and reduced the formation of tumorspheres as a potent anti-lung cancer agent. Citation Format: Chun-Chia Cheng, Jungshan Chang, Huan-Chau Lin, Ai-Sheng Ho, Ken-Hong Lim, Chun-Chao Chang, Yi-Fang Chang, Cheng-Wen Wu. EGFR induces ILF3 and G9a expressions to maintain Oct4-mediated stemness property in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 934. doi:10.1158/1538-7445.AM2017-934
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- 2017
29. Discovery of Tumor Markers for Gastric Cancer by Proteomics
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Jan-Sing Hsieh, Deng-Chyang Wu, Wen-Ming Wang, Shui-Cheng Lee, Jaw-Yuan Wang, Jeng-Yih Wu, and Chun-Chia Cheng
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Proteomics ,Male ,Pathology ,lcsh:Medicine ,Protein expression ,Two-Dimensional Difference Gel Electrophoresis ,chemistry.chemical_compound ,Gastrointestinal Cancers ,lcsh:Science ,Endoplasmic Reticulum Chaperone BiP ,Gel electrophoresis ,Aged, 80 and over ,Gastrointestinal tract ,Multidisciplinary ,Middle Aged ,Immunohistochemistry ,Blot ,Oncology ,Medicine ,Female ,Immunohistochemical Analysis ,Research Article ,medicine.medical_specialty ,Immunology ,Gastroenterology and Hepatology ,Biology ,Diagnostic Medicine ,Stomach Neoplasms ,Gastrointestinal Tumors ,medicine ,Cancer Detection and Diagnosis ,Early Detection ,Biomarkers, Tumor ,Humans ,Aged ,Neoplasm Staging ,lcsh:R ,Cancer ,Cancers and Neoplasms ,Glutathione ,medicine.disease ,Gastric Cancer ,chemistry ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Immunologic Techniques ,lcsh:Q ,Biomarkers ,General Pathology - Abstract
Gastric cancer (GC) has a high rate of morbidity and mortality among various cancers worldwide. The development of noninvasive diagnostic methods or technologies for tracking the occurrence of GC is urgent, and searching reliable biomarkers is considered.This study intended to directly discover differential biomarkers from GC tissues by two-dimension-differential gel electrophoresis (2D-DIGE), and further validate protein expression by western blotting (WB) and immunohistochemistry (IHC).Pairs of GC tissues (gastric cancer tissues and the adjacent normal tissues) obtained from surgery was investigated for 2D-DIEG.Five proteins wereconfirmed by WB and IHC, including glucose-regulated protein 78 (GRP78), glutathione s-transferase pi (GSTpi), apolipoprotein AI (ApoAI), alpha-1 antitrypsin (A1AT) and gastrokine-1 (GKN-1). Among the results, GRP78, GSTpi and A1ATwere significantlyup-regulated and down-regulated respectively in gastric cancer patients. Moreover, GRP78 and ApoAI were correlated with A1AT for protein expressions.This study presumes these proteins could be candidates of reliable biomarkers for gastric cancer.
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- 2014
30. Novel biomarkers predict liver fibrosis in hepatitis C patients: alpha 2 macroglobulin, vitamin D binding protein and apolipoprotein AI
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Shui-Cheng Lee, Ai-Sheng Ho, Chun-Chia Cheng, Jing-Ying Lee, Meng-Lun Liu, Chia-Chi Wang, and Wen-Ming Wang
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Liver Cirrhosis ,medicine.medical_specialty ,Pathology ,Vitamin D-binding protein ,Difference gel electrophoresis ,Endocrinology, Diabetes and Metabolism ,Blotting, Western ,Clinical Biochemistry ,lcsh:Medicine ,Gastroenterology ,alpha-2-Macroglobulin ,Fibrosis ,Internal medicine ,medicine ,Vitamin D and neurology ,Humans ,Electrophoresis, Gel, Two-Dimensional ,alpha-Macroglobulins ,Pharmacology (medical) ,Molecular Biology ,Biochemistry, medical ,Apolipoprotein A-I ,medicine.diagnostic_test ,biology ,Vitamin D-Binding Protein ,Research ,Biochemistry (medical) ,lcsh:R ,General Medicine ,Hepatitis C ,Cell Biology ,medicine.disease ,Blot ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Liver biopsy ,biology.protein ,Biomarkers - Abstract
Background The gold standard of assessing liver fibrosis is liver biopsy, which is invasive and not without risk. Therefore, searching for noninvasive serologic biomarkers for liver fibrosis is an importantly clinical issue. Methods A total of 16 healthy volunteers and 45 patients with chronic hepatitis C virus (HCV) were enrolled (F0: n = 16, F1: n = 7, F2: n = 17, F3: n = 8 and F4: n = 13, according to the METAVIR classification). Three serum samples of each fibrotic stage were analyzed by two-dimension difference gel electrophoresis (2D-DIGE). The differential proteins were identified by the cooperation of MALDI-TOF/TOF and MASCOT; then western blotting and Bio-Plex Suspension Array were used to quantify the protein levels. Results Three prominent candidate biomarkers were identified: alpha 2 macroglobulin (A2M) is up regulated; vitamin D binding protein (VDBP) and apolipoprotein AI (ApoAI) are down regulated. The serum concentration of A2M was significantly different among normal, mild (F1/F2) and advanced fibrosis (F3/F4) (p < 0.01). The protein levels of VDBP and ApoAI were significantly higher in normal/mild fibrosis, when compared to those in advanced fibrosis (both p < 0.01). Conclusions This study not only reveals three putative biomarkers of liver fibrosis (A2M, VDBP and ApoAI) but also proves the differential expressions of those markers in different stages of fibrosis. We expect that combination of these novel biomarkers could be applied clinically to predict the stage of liver fibrosis without the need of liver biopsy.
- Published
- 2010
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