28 results on '"Pak Shing Kwan"'
Search Results
2. Supplementary Table 2 from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
- Author
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Kwok Wah Chan, Xin-Yuan Guan, Juergen R. Vielkind, Ming Tat Ling, Kwan Ho Tang, Mingxia Yan, Terence K. Lee, Pak Shing Kwan, Yuen Piu Chan, and Stephanie Ma
- Abstract
Supplementary Table 2 from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
- Published
- 2023
3. Data from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
- Author
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Kwok Wah Chan, Xin-Yuan Guan, Juergen R. Vielkind, Ming Tat Ling, Kwan Ho Tang, Mingxia Yan, Terence K. Lee, Pak Shing Kwan, Yuen Piu Chan, and Stephanie Ma
- Abstract
Expression of microRNA genes is profoundly altered in cancer but their role in the development of androgen-independent prostate cancer has received limited attention as yet. In this study, we report a functional impact in prostate cancer cells for overexpression of the microRNA miR-616, which occurred consistently in cells that were androgen-independent (AI) versus androgen-dependent (AD). miR-616 overexpression was confirmed in malignant prostate tissues as opposed to benign prostate specimens. Stable miR-616 overexpression in LNCaP cells by a lentiviral-based approach stimulated AI prostate cancer cell proliferation in vitro whereas concomitantly reducing androgen-induced cell growth. More importantly, miR-616 overexpressing LNCaP cells overcame castration resistance as shown by an enhanced ability to proliferate in vivo after bilateral orchiectomy. Conversely, antagonizing miR-616 in AI prostate cancer cells yielded opposite effects. Microarray profiling and bioinformatics analysis identified the tissue factor pathway inhibitor TFPI-2 mRNA as a candidate downstream target of miR-616. In support of this candidacy, we documented interactions between miR-616 and the 3′UTR of TFPI-2 and determined TFPI-2 expression to be inversely correlated to miR-616 in a series of prostate cell lines and clinical specimens. Notably, reexpression of TFPI-2 in LNCaP cells with stable miR-616 overexpression rescued the AD phenotype, as shown by a restoration of androgen dependence and cell growth inhibition. Taken together, our findings define a functional involvement for miR-616 and TFPI-2 in the development and maintenance of androgen-independent prostate cancer. Cancer Res; 71(2); 583–92. ©2011 AACR.
- Published
- 2023
4. Supplementary Figure 2 from Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
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Stephanie Ma, Xin-Yuan Guan, Si Lok, Yan-Ru Qin, Li Fu, Kwan Ho Tang, Pak Shing Kwan, Jin-Na Chen, Kai Yau Wong, Jessie Y.J. Bao, Kwok Wah Chan, and Man Tong
- Abstract
PDF file, 720K, Detection of DNA copy number change of Rab25 by dual-color fluorescent in situ hybridization (FISH) in ESCC cell lines KYSE520, EC109 and formalin-fixed paraffin-embedded ESCC clinical tissue specimens (#1 and #2) with no or low Rab25 expression. BAC probe to Rab25 and the control reference probe to the centromere of chromosome 1 are represented by red and green signals, respectively. Magnification at 1000x.
- Published
- 2023
5. Supplementary Information from Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
- Author
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Stephanie Ma, Xin-Yuan Guan, Si Lok, Yan-Ru Qin, Li Fu, Kwan Ho Tang, Pak Shing Kwan, Jin-Na Chen, Kai Yau Wong, Jessie Y.J. Bao, Kwok Wah Chan, and Man Tong
- Abstract
PDF file, 153K, Supplementary Materials and Methods, Tables, Figure Legends, References
- Published
- 2023
6. Supplementary Figure Legend and Table 1 - 5 from A CD90+ Tumor-Initiating Cell Population with an Aggressive Signature and Metastatic Capacity in Esophageal Cancer
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Xin Yuan Guan, Stephanie Ma, Kwok Wah Chan, Simon Law, Daniel K. Tong, Maria L. Lung, Hong Lok Lung, Sai Wah Tsao, Yan Ru Qin, Li Fu, Pak Shing Kwan, Yuen Piu Chan, Man Tong, Yong Dong Dai, and Kwan Ho Tang
- Abstract
DOC file - 322K, Supplemental Table 1. Primer sequences for real-time qPCR analyses. Supplemental Table 2. RPKM values of other reported CSC markers in the original 3 pairs of non-tumor (N) and ESCC (T) clinical samples (Patients #16, #18 and #19) used for RNA-Seq profiling. Supplemental Table 3. Cancer stem cell marker expression (CD90, CD44 and p75NTR / CD271) in a panel of ESCC cell lines. Supplemental Table 4. Clinicopathological correlation of CD44 and p75NTR / CD271 expression in ESCC. Supplemental Table 5. List of deregulated genes in CD90+ vs. CD90- cells in ESCC cells KYSE140 (cut off ≥ 3 folds).
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- 2023
7. Supplementary Figure 2 from A CD90+ Tumor-Initiating Cell Population with an Aggressive Signature and Metastatic Capacity in Esophageal Cancer
- Author
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Xin Yuan Guan, Stephanie Ma, Kwok Wah Chan, Simon Law, Daniel K. Tong, Maria L. Lung, Hong Lok Lung, Sai Wah Tsao, Yan Ru Qin, Li Fu, Pak Shing Kwan, Yuen Piu Chan, Man Tong, Yong Dong Dai, and Kwan Ho Tang
- Abstract
PDF file - 1414K, Supplemental Figure 2. CD90, CD44 and p75NTR / CD271 expression in matched non-tumor (N) and primary ESCC (T) (n = 33) as detected by real-time qPCR.
- Published
- 2023
8. Supplementary Figure Legend from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
- Author
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Kwok Wah Chan, Xin-Yuan Guan, Juergen R. Vielkind, Ming Tat Ling, Kwan Ho Tang, Mingxia Yan, Terence K. Lee, Pak Shing Kwan, Yuen Piu Chan, and Stephanie Ma
- Abstract
Supplementary Figure Legend from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
- Published
- 2023
9. Data from Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
- Author
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Stephanie Ma, Xin-Yuan Guan, Si Lok, Yan-Ru Qin, Li Fu, Kwan Ho Tang, Pak Shing Kwan, Jin-Na Chen, Kai Yau Wong, Jessie Y.J. Bao, Kwok Wah Chan, and Man Tong
- Abstract
Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK–Raf–MEK1/2–ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment. Cancer Res; 72(22); 6024–35. ©2012 AACR.
- Published
- 2023
10. Supplementary Figure 1 from Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
- Author
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Stephanie Ma, Xin-Yuan Guan, Si Lok, Yan-Ru Qin, Li Fu, Kwan Ho Tang, Pak Shing Kwan, Jin-Na Chen, Kai Yau Wong, Jessie Y.J. Bao, Kwok Wah Chan, and Man Tong
- Abstract
PDF file, 2272K, Expression tiling of Rab25 in 6 unpaired ESCC and non-tumor clinical samples.
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- 2023
11. Supplementary Figure 1 from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
- Author
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Kwok Wah Chan, Xin-Yuan Guan, Juergen R. Vielkind, Ming Tat Ling, Kwan Ho Tang, Mingxia Yan, Terence K. Lee, Pak Shing Kwan, Yuen Piu Chan, and Stephanie Ma
- Abstract
Supplementary Figure 1 from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
- Published
- 2023
12. Supplementary References from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
- Author
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Kwok Wah Chan, Xin-Yuan Guan, Juergen R. Vielkind, Ming Tat Ling, Kwan Ho Tang, Mingxia Yan, Terence K. Lee, Pak Shing Kwan, Yuen Piu Chan, and Stephanie Ma
- Abstract
Supplementary References from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
- Published
- 2023
13. Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133
- Author
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Xin Yuan Guan, Tsun Ming Fung, Kai Yu Ng, Yuen Piu Chan, Stephanie Ma, Pak Shing Kwan, Yunfei Yuan, Terence K. Lee, Stella Chai, Nathalie Wong, Man Tong, and Dan Xie
- Subjects
Oncology ,medicine.medical_specialty ,Cellular pathology ,Carcinoma, Hepatocellular ,Angiogenesis ,Population ,miR-142-3p ,Mice, Nude ,Biology ,Transfection ,tumor-initiating cells ,Mice ,Antigens, CD ,Cancer stem cell ,Internal medicine ,medicine ,Carcinoma ,Animals ,Humans ,AC133 Antigen ,CD133 ,education ,neoplasms ,Glycoproteins ,education.field_of_study ,Liver Neoplasms ,Cancer ,Hep G2 Cells ,medicine.disease ,digestive system diseases ,MicroRNAs ,Hepatocellular carcinoma ,Immunology ,Neoplastic Stem Cells ,Heterografts ,Stem cell ,Peptides ,Research Paper - Abstract
Tumor relapse after therapy typifies hepatocellular carcinoma (HCC) and is believed to be attributable to residual cancer stem cells (CSCs) that survive treatment. We have previously identified a CSC population derived from HCC that is characterized by CD133. Despite our growing knowledge of the importance of this subset of cells in driving HCC, the regulatory mechanism of CD133 is not known. Epigenetic changes are believed to be essential in the control of cancer and stem cells. Here, we report the epigenetic regulation of CD133 by miR-142-3p. The interaction between CD133 and miR-142-3p was identified by in silico prediction and substantiated by luciferase reporter analysis. Expression of CD133 was found to be inversely correlated with miR-142-3p in HCC clinical samples as well as in cell lines. Importantly, lower miR-142-3p expression in HCC was significantly associated with worst survival. Functional studies with miR-142-3p stably transduced in HCC cells demonstrated a diminished ability to self-renew, initiate tumor growth, invade, migrate, induce angiogenesis and resist chemotherapy. Rescue experiments whereby CD133 and miR-142-3p is simultaneously overexpressed compensated the deregulated ability of the cells to confer these features. Thus, miR-142-3p directly targets CD133 to regulate its ability to confer cancer and stem cell-like features in HCC., published_or_final_version
- Published
- 2014
14. Daxx regulates mitotic progression and prostate cancer predisposition
- Author
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Yung-Tuen Chiu, Chi Chiu Lau, Pak Shing Kwan, Kai Dun Tang, Ming-Tat Ling, Ji Liu, Cornelia Man, and Yong-Chuan Wong
- Subjects
Male ,Cancer Research ,Cdc20 Proteins ,Adenomatous Polyposis Coli Protein ,Mitosis ,Cell Cycle Proteins ,CDC20 ,Biology ,Metastasis ,Prostate cancer ,Death-associated protein 6 ,Antigens, CD ,Cell Line, Tumor ,Chromosomal Instability ,medicine ,Humans ,Neoplasm Metastasis ,RNA, Small Interfering ,Adaptor Proteins, Signal Transducing ,Cell Cycle ,Nuclear Proteins ,Prostatic Neoplasms ,Cancer ,Cell Cycle Checkpoints ,General Medicine ,Cell cycle ,Cadherins ,medicine.disease ,HEK293 Cells ,Mutation ,Immunology ,Cancer research ,RNA Interference ,Ectopic expression ,Neoplasm Grading ,Anaphase-promoting complex ,Co-Repressor Proteins ,HeLa Cells ,Molecular Chaperones - Abstract
Mitotic progression of mammalian cells is tightly regulated by the E3 ubiquitin ligase anaphase promoting complex (APC)/C. Deregulation of APC/C is frequently observed in cancer cells and is suggested to contribute to chromosome instability and cancer predisposition. In this study, we identified Daxx as a novel APC/C inhibitor frequently overexpressed in prostate cancer. Daxx interacts with the APC/C coactivators Cdc20 and Cdh1 in vivo, with the binding of Cdc20 dependent on the consensus destruction boxes near the N-terminal of the Daxx protein. Ectopic expression of Daxx, but not the D-box deleted mutant (DaxxΔD-box), inhibited the degradation of APC/Cdc20 and APC/Cdh1 substrates, leading to a transient delay in mitotic progression. Daxx is frequently upregulated in prostate cancer tissues; the expression level positively correlated with the Gleason score and disease metastasis (P = 0.027 and 0.032, respectively). Furthermore, ectopic expression of Daxx in a non-malignant prostate epithelial cell line induced polyploidy under mitotic stress. Our data suggest that Daxx may function as a novel APC/C inhibitor, which promotes chromosome instability during prostate cancer development.
- Published
- 2012
15. Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
- Author
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Si Lok, KY Wong, Man Tong, Kwan Ho Tang, Xin Yuan Guan, Stephanie Ma, Kwok Wah Chan, Pak Shing Kwan, Jessie Y.J. Bao, Jin Na Chen, Li Fu, and Yan Ru Qin
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Esophageal Neoplasms ,Tumor suppressor gene ,MAP Kinase Signaling System ,Molecular Sequence Data ,Down-Regulation ,Mice, Nude ,Endocytic recycling ,Transcriptome ,Mice ,Downregulation and upregulation ,Cell Movement ,Cell Line, Tumor ,Internal medicine ,Carcinoma ,medicine ,Animals ,Humans ,Genes, Tumor Suppressor ,Neoplasm Invasiveness ,Promoter Regions, Genetic ,neoplasms ,Base Sequence ,Neovascularization, Pathologic ,business.industry ,Gene Expression Profiling ,DNA Methylation ,Esophageal cancer ,medicine.disease ,digestive system diseases ,Gene expression profiling ,rab GTP-Binding Proteins ,DNA methylation ,Carcinoma, Squamous Cell ,Cancer research ,business - Abstract
Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK–Raf–MEK1/2–ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment. Cancer Res; 72(22); 6024–35. ©2012 AACR.
- Published
- 2012
16. miR-130b Promotes CD133+ Liver Tumor-Initiating Cell Growth and Self-Renewal via Tumor Protein 53-Induced Nuclear Protein 1
- Author
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Paul B.S. Lai, Kwan Ho Tang, Antonia Castilho, Ka Fai To, Nathalie Wong, Stephanie Ma, Pak Shing Kwan, Xin Yuan Guan, Kwok Wah Chan, Irene Ng, Terence K. Lee, Kwan Man, Bo-Jian Zheng, Yuen Piu Chan, and Chung Mau Lo
- Subjects
Adult ,Male ,Carcinoma, Hepatocellular ,Liver tumor ,Mice, SCID ,Biology ,Mice ,Antigen ,Antigens, CD ,Cancer stem cell ,Cell Line, Tumor ,microRNA ,Genetics ,medicine ,Animals ,Humans ,Gene silencing ,AC133 Antigen ,neoplasms ,Heat-Shock Proteins ,Aged ,Cell Proliferation ,Glycoproteins ,Aged, 80 and over ,Cell growth ,Liver Neoplasms ,Nuclear Proteins ,Cell Biology ,Middle Aged ,medicine.disease ,In vitro ,carbohydrates (lipids) ,MicroRNAs ,Liver ,Cell culture ,embryonic structures ,Immunology ,Neoplastic Stem Cells ,Cancer research ,Molecular Medicine ,Female ,Carrier Proteins ,Peptides - Abstract
A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor, called tumor-initiating cells (TICs) or cancer stem cells (CSCs). Here we describe the identification and characterization of such cells from hepatocellular carcinoma (HCC) using the marker CD133. CD133 accounts for approximately 1.3%-13.6% of the cells in the bulk tumor of human primary HCC samples. When compared with their CD133⁻ counterparts, CD133(+) cells not only possess the preferential ability to form undifferentiated tumor spheroids in vitro but also express an enhanced level of stem cell-associated genes, have a greater ability to form tumors when implanted orthotopically in immunodeficient mice, and can be serially passaged into secondary animal recipients. Xenografts resemble the original human tumor and maintain a similar percentage of tumorigenic CD133(+) cells. Quantitative PCR analysis of 41 separate HCC tissue specimens with follow-up data found that CD133(+) tumor cells were frequently detected at low quantities in HCC, and their presence was also associated with worse overall survival and higher recurrence rates. Subsequent differential microRNA expression profiling of CD133(+) and CD133⁻ cells from human HCC clinical specimens and cell lines identified an overexpression of miR-130b in CD133(+) TICs. Functional studies on miR-130b lentiviral-transduced CD133⁻ cells demonstrated superior resistance to chemotherapeutic agents, enhanced tumorigenicity in vivo, and a greater potential for self renewal. Conversely, antagonizing miR-130b in CD133(+) TICs yielded an opposing effect. The increased miR-130b paralleled the reduced TP53INP1, a known miR-130b target. Silencing TP53INP1 in CD133⁻ cells enhanced both self renewal and tumorigenicity in vivo. Collectively, miR-130b regulates CD133(+) liver TICs, in part, via silencing TP53INP1.
- Published
- 2010
17. Roles of Daxx in mitosis and prostate carcinogenesis
- Author
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Pak-shing. Kwan
- Subjects
Oncology ,medicine.medical_specialty ,Death-associated protein 6 ,Internal medicine ,medicine ,Biology ,Prostate carcinogenesis ,Mitosis - Published
- 2012
18. CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling
- Author
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Irene Oi-Lin Ng, Carol Man Tong, Pak Shing Kwan, Paul B.S. Lai, Yuen Piu Chan, Ka Fai To, Kwan Man, Stephanie Ma, Kwok Wah Chan, Terence K. Lee, Chung Mau Lo, Kwan Ho Tang, and Xin Yuan Guan
- Subjects
MAPK/ERK pathway ,Liver tumor ,Carcinoma, Hepatocellular ,Angiogenesis ,Chemokine CXCL1 ,Population ,Mice, Nude ,Biology ,medicine.disease_cause ,Mice ,Antigens, CD ,Cell Line, Tumor ,medicine ,Animals ,Hepatectomy ,Humans ,Interleukin 8 ,AC133 Antigen ,education ,Cells, Cultured ,Neurotensin ,Cell Proliferation ,Glycoproteins ,Feedback, Physiological ,Mitogen-Activated Protein Kinase Kinases ,education.field_of_study ,Hepatology ,Neovascularization, Pathologic ,Cell growth ,Interleukin-8 ,Liver Neoplasms ,medicine.disease ,Xenograft Model Antitumor Assays ,CXCL1 ,Liver ,Cancer research ,Neoplastic Stem Cells ,Carcinogenesis ,Peptides ,Signal Transduction - Abstract
A novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem-like cells, called tumor-initiating cells (TICs). We previously identified a TIC population derived from hepatocellular carcinoma (HCC) that is characterized by membrane expression of CD133. Here, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome-wide microarray analysis. A significantly dysregulated interleukin-8 (IL-8) signaling network was identified in CD133+ liver TICs obtained from HCC clinical samples and cell lines. IL-8 was found to be overexpressed at both the genomic and proteomic levels in CD133+ cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL-8 secretion in CD133+ liver TICs to exhibit a greater ability to self-renew, induce tumor angiogenesis, and initiate tumors. In further support of these observations, IL-8 repression in CD133+ liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL-8 functional network identified neurotensin (NTS) and CXCL1 to be preferentially expressed in CD133+ liver TICs. Addition of exogenous NTS resulted in concomitant up-regulation of IL-8 and CXCL1 with simultaneous activation of p-ERK1/2 and RAF-1, both key components of the mitogen-activated protein kinase (MAPK) pathway. Enhanced IL-8 secretion by CD133+ liver TICs can in turn activate an IL-8-dependent feedback loop that signals through the MAPK pathway. Further, in its role as a liver TIC marker CD133 also plays a functional part in regulating tumorigenesis of liver TICs by way of regulating NTS, IL-8, CXCL1, and MAPK signaling. Conclusion: CD133+ liver TICs promote angiogenesis, tumorigenesis, and self-renewal through NTS-induced activation of the IL-8 signaling cascade. (Hepatology 2012)
- Published
- 2011
19. MicroRNA-616 induces androgen-independent growth of prostate cancer cells by suppressing expression of tissue factor pathway inhibitor TFPI-2
- Author
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Pak Shing Kwan, Mingxia Yan, Xin Yuan Guan, Stephanie Ma, Kwok Wah Chan, Terence K. Lee, Kwan Ho Tang, Juergen R. Vielkind, Yuen Piu Chan, and Ming-Tat Ling
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Neoplasms, Hormone-Dependent ,Prostatic Hyperplasia ,Mice, Nude ,Cell Growth Processes ,Biology ,Prostate cancer ,Mice ,Tissue factor pathway inhibitor ,Prostate ,Internal medicine ,Cell Line, Tumor ,microRNA ,LNCaP ,medicine ,Animals ,Humans ,education ,Glycoproteins ,education.field_of_study ,Cell growth ,Cancer ,Prostatic Neoplasms ,medicine.disease ,Tissue-factor-pathway inhibitor 2 ,MicroRNAs ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Cancer research ,Androgens ,Orchiectomy - Abstract
Expression of microRNA genes is profoundly altered in cancer but their role in the development of androgen-independent prostate cancer has received limited attention as yet. In this study, we report a functional impact in prostate cancer cells for overexpression of the microRNA miR-616, which occurred consistently in cells that were androgen-independent (AI) versus androgen-dependent (AD). miR-616 overexpression was confirmed in malignant prostate tissues as opposed to benign prostate specimens. Stable miR-616 overexpression in LNCaP cells by a lentiviral-based approach stimulated AI prostate cancer cell proliferation in vitro whereas concomitantly reducing androgen-induced cell growth. More importantly, miR-616 overexpressing LNCaP cells overcame castration resistance as shown by an enhanced ability to proliferate in vivo after bilateral orchiectomy. Conversely, antagonizing miR-616 in AI prostate cancer cells yielded opposite effects. Microarray profiling and bioinformatics analysis identified the tissue factor pathway inhibitor TFPI-2 mRNA as a candidate downstream target of miR-616. In support of this candidacy, we documented interactions between miR-616 and the 3′UTR of TFPI-2 and determined TFPI-2 expression to be inversely correlated to miR-616 in a series of prostate cell lines and clinical specimens. Notably, reexpression of TFPI-2 in LNCaP cells with stable miR-616 overexpression rescued the AD phenotype, as shown by a restoration of androgen dependence and cell growth inhibition. Taken together, our findings define a functional involvement for miR-616 and TFPI-2 in the development and maintenance of androgen-independent prostate cancer. Cancer Res; 71(2); 583–92. ©2011 AACR.
- Published
- 2011
20. Abstract LB-53: Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133
- Author
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Yuen Piu Chan, Nathalie Wong, Kai Y. Ng, Man Tong, Xin Yuan Guan, Pak Shing Kwan, Stella Chai, Terence Kin Wah Lee, and Stephanie Ma
- Subjects
Cancer Research ,education.field_of_study ,business.industry ,Liver cell ,Population ,Cancer ,medicine.disease ,Oncology ,Cancer stem cell ,Hepatocellular carcinoma ,DNA methylation ,Immunology ,medicine ,Cancer research ,Epigenetics ,Stem cell ,education ,business ,neoplasms - Abstract
Tumor relapse after therapy typifies hepatocellular carcinoma (HCC) and is believed to be attributable to residual cancer stem cells (CSCs) that survive initial treatment. We have previously identified a CSC population derived from HCC that is characterized by the expression of the transmembrane glycoprotein, CD133. Despite our growing knowledge of the importance of a functional CD133+ liver CSC subset in driving HCC, the regulatory mechanism of CD133 is not known. Epigenetic changes are believed to be essential in the control of cancer and stem cells. We report here the dynamic epigenetic regulation of the functional liver CSC marker CD133 by promoter methylation and miR-142-3p regulation. Unlike in other tumor types, we found DNA methylation to only play a minor role in the control of CD133 expression in HCC. More importantly, our results revealed that miR-142-3p plays an integral part in the direct targeting of CD133. The interaction between the 3’UTR of CD133 and miR-142-3p was identified by in silico prediction and substantiated by luciferase reporter analysis. Expression of CD133 was found to be inversely correlated with miR-142-3p in a panel of liver cell lines and HCC clinical samples. Functional studies with miR-142-3p stably transduced in HCC cells demonstrated a diminished ability to self-renew, initiate tumor growth, invade, migrate, induce capillary tube formation in endothelial cells and resist standard chemotherapy. Rescue experiments whereby CD133 and miR-142-3p is simultaneously overexpressed compensated the deregulated ability of the cells to confer these cancer and stem cell-like features. In summary, our findings suggestion promoter methylation to only play a minor role in the regulation of CD133 in HCC; and that miR-142-3p directly targets CD133 to regulate its ability to confer cancer and stem cell-like features in HCC. Citation Format: Kai Yu Ng, Stella Chai, Man Tong, Pak Shing Kwan, Yuen Piu Chan, Terence Kin Wah Lee, Nathalie Wong, Xin-Yuan Guan, Stephanie Ma. Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133. [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 LB-53. doi:10.1158/1538-7445.AM2014-LB-53
- Published
- 2014
21. Abstract 3023: RNA-Seq identifies neuropilin-2 as a novel oncogene in esophageal squamous cell carcinoma
- Author
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Man Tong, Stephanie Ma, Yuen Piu Chan, Xin Yuan Guan, Pak Shing Kwan, and Tsun Ming Fung
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Tissue microarray ,Oncogene ,Angiogenesis ,Cell growth ,Cancer ,Biology ,Esophageal cancer ,medicine.disease ,digestive system diseases ,Oncology ,Neuropilin 1 ,medicine ,Neuropilin ,Cancer research - Abstract
Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is one of the most common and deadliest cancers in the world, with survival rates of less than 15%. Like many other solid tumors, the pathogenesis of ESCC is believed to be a multistep process with accumulation of numerous genetic alterations involving de-regulation of both tumor-suppressor genes and oncogenes. An understanding of the molecular events that result in the development and progression of the disease may lead to treatments that will increase survival rates of ESCC patients. Recent advances in sequencing technologies offer the opportunity to characterize the cancer genome at unprecedented depth and sensitivity. RNA-Seq has proved an effective means of precisely quantifying the changing expression levels of each transcript. In this study, we performed integrative RNA-Seq analysis on 3 paired patient-derived non-tumor and ESCC clinical specimens and discovered a number of commonly differentially expressed genes, of which included a significantly de-regulated neuropilin (NRP) family including neuropilin-1 (NRP1) and neuropilin-2 (NRP2). NRP is a single-spanned membrane glycoprotein. Members of the family have previously been shown to play an important role in various cancer types and to be a co-receptor of vascular endothelial growth factors. Yet to date, its role in ESCC has not been explored. Up-regulation of both NRP1 and NRP2 in ESCC was subsequently validated in the original 3 pairs of clinical samples used for RNA-Seq as well as in a larger cohort of samples (n = 40) by qPCR. Given that NRP2 de-regulation in ESCC is more significant, we chose to first focus our study on this member of the family. Immunohistochemical studies likewise found NRP2 to be up-regulated in ESCC as compared with its non-tumor counterparts in a tissue microarray. Consistently, expression studies in a panel of esophageal cell lines found NRP2 to be expressed at a significantly higher level in 7 of the 8 ESCC cell lines examined compared with immortalized normal esophageal cell lines, NE1 and NE3. Functional studies in ESCC cells, KYSE180 and KYSE140, with NRP2 stably repressed by lentiviral-based shRNA approach impaired proliferation and metastatic abilities in vitro, as demonstrated by foci formation and chemotaxis migration assays, respectively. Moreover, conditioned medium collected from NRP2 repressed cells displayed a reduced ability to induce capillary tube formation in HUVEC cells. These results suggest that NRP2 plays an important role in regulating cell proliferation, migration and angiogenesis in ESCC. Additional work on the mechanism by which NRP2 drives ESCC and the effectiveness of the use of a NRP2 neutralizing antibody against ESCC is currently being studied. We believe with further study, NRP2 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target for ESCC treatment. Citation Format: Tsun Ming Fung, Man Tong, Pak Shing Kwan, Yuen Piu Chan, Xin-Yuan Guan, Stephanie Ma. RNA-Seq identifies neuropilin-2 as a novel oncogene in esophageal squamous cell carcinoma. [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 3023. doi:10.1158/1538-7445.AM2013-3023
- Published
- 2013
22. Identification of PTK6, via RNA Sequencing Analysis, as a Suppressor of Esophageal Squamous Cell Carcinoma
- Author
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Jessie Y.J. Bao, Amy Hin Yan Tong, Stephanie Ma, Kwok Wah Chan, Si Lok, Sai Wah Tsao, Yan Ru Qin, Na Zhang, Pak Shing Kwan, Li Fu, Xin Yuan Guan, Yuen Piu Chan, and Carol Man Tong
- Subjects
Male ,Esophageal Neoplasms ,Transcription, Genetic ,Epigenesis, Genetic ,Histones ,Glycogen Synthase Kinase 3 ,Mice ,Cell Movement ,Phosphorylation ,Promoter Regions, Genetic ,beta Catenin ,Gene knockdown ,Gastroenterology ,Acetylation ,Middle Aged ,Protein-Tyrosine Kinases ,Cell cycle ,Extracellular Matrix ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Gene Knockdown Techniques ,DNA methylation ,Carcinoma, Squamous Cell ,Female ,RNA Interference ,PTK6 ,Signal Transduction ,medicine.drug ,Adult ,Mice, Nude ,Biology ,Transfection ,Gene Expression Regulation, Enzymologic ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,neoplasms ,Protein kinase B ,Cell Proliferation ,Glycogen Synthase Kinase 3 beta ,Hepatology ,Sequence Analysis, RNA ,Cell growth ,Gene Expression Profiling ,Tumor Suppressor Proteins ,DNA Methylation ,G1 Phase Cell Cycle Checkpoints ,Molecular biology ,digestive system diseases ,Trichostatin A ,Cell culture ,Cancer research ,Proto-Oncogene Proteins c-akt - Abstract
Background & Aims Esophageal squamous cell carcinoma (ESCC) is the most commonly observed histologic subtype of esophageal cancer. ESCC is believed to develop via accumulation of numerous genetic alterations, including inactivation of tumor suppressor genes and activation of oncogenes. We searched for transcripts that were altered in human ESCC samples compared with nontumor tissues. Methods We performed integrative transcriptome sequencing (RNA-Seq) analysis using ESCC samples from 3 patients and adjacent nontumor tissues to identify transcripts that were altered in ESCC tissue. We performed molecular and functional studies of the transcripts identified and investigated the mechanisms of alteration. Results We identified protein tyrosine kinase 6 ( PTK6 ) as a transcript that was significantly down-regulated in ESCC tissues and cell lines compared with nontumor tissues or immortalized normal esophageal cell lines. The promoter of the PTK6 gene was inactivated in ESCC tissues at least in part via hypermethylation and histone deacetylation. Knockdown of PTK6 in KYSE30 ESCC cells using small hairpin RNAs increased their ability to form foci, migrate, and invade extracellular matrix in culture and form tumors in nude mice. Overexpression of PTK6 in these cells reduced their proliferation in culture and tumor formation in mice. PTK6 reduced phosphorylation of Akt and glycogen synthase kinase (GSK)3β, leading to activation of β-catenin. Conclusions PTK6 was identified as a transcript that is down-regulated in human ESCC tissues via epigenetic modification at the PTK6 locus. Its product appears to regulate cell proliferation by reducing phosphorylation of Akt and GSK3β, leading to activation of β-catenin. Reduced levels of PTK6 promote growth of xenograft tumors in mice; it might be developed as a marker of ESCC.
- Published
- 2012
23. Abstract 2105: RNA-seq identifies protein tyrosine kinase 6 (PTK6) as a candidate tumor-suppressor gene in esophageal squamous cell carcinoma
- Author
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Yuen Piu Chan, Xin Yuan Guan, Carol Man Tong, Kwan Ho Tang, Li Fu, Pak Shing Kwan, Stephanie Ma, and Kwok Wah Chan
- Subjects
Cancer Research ,Tumor suppressor gene ,Bisulfite sequencing ,Cancer ,Esophageal cancer ,Biology ,medicine.disease ,Molecular biology ,Candidate Tumor Suppressor Gene ,Oncology ,medicine ,Immunohistochemistry ,PTK6 ,Gene - Abstract
Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is one of the most common and deadliest cancers in the world, with survival rates of less than 15%. Like many other solid tumors, the pathogenesis of ESCC is also believed to be a multistep process with accumulation of numerous genetic alterations involving inactivation of tumor-suppressor genes and activation of oncogenes. An understanding of the molecular events that result in the development and progression of the disease may lead to treatments that will increase survival rates of ESCC patients. Recent advances in sequencing technologies offer the opportunity to characterize the cancer genome at unprecedented depth and sensitivity. Large-scale transcriptome sequencing (RNA-Seq) has proved an effective means of precisely quantifying the changing expression levels of each transcript. In this study, we performed integrative RNA-Seq analysis on 14 patient-derived ESCC clinical specimens (4 paired ESCC and their adjacent non-tumorous (NT) counterparts, 1 unpaired NT and 5 unpaired ESCC) and discovered a number of commonly differentially expressed genes in ESCC compared with NT tissues. A total of 526 genes were found to be significantly aberrantly expressed, including 452 genes that were up-regulated and 74 genes that were down-regulated. One candidate tumor suppressor gene, protein tyrosine kinase 6 (PTK6), was chosen for further characterization. By both quantitative real-time PCR and immunohistochemistry analysis, PTK6 was found to be significantly down-regulated in a larger cohort of ESCC tumors compared with NT counterparts. Consistently, expression studies in a panel of esophageal cell lines found PTK6 to be either absent or expressed in low amounts in all eight ESCC cell lines examined compared with two immortalized normal esophageal cell lines, NE1 and NE3. Down-regulation of PTK6 in both ESCC cell lines and clinical samples was found to be significantly associated with promoter hypermethylation, as evident by results obtained from studies involving demethylation treatment with 5-aza-dC, methylation specific PCR as well as bisulfite genomic sequencing. Functional studies in ESCC cell lines, EC109 and KYSE30, with PTK6 stably repressed by lentiviral-based approach stimulated both in vitro and in vivo tumorigenicity ability of the cells including foci formation, colony formation in soft agar as well as tumor formation in nude mice. Taken together, our findings define a function for PTK6 as an important tumor suppressor gene in ESCC development. Additional work on the mechanism by which PTK6 drives ESCC is currently being studied in our laboratory. 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 2105. doi:10.1158/1538-7445.AM2011-2105
- Published
- 2011
24. Abstract 2451: CD133+ liver tumor-initiating cells promote tumor growth, angiogenesis and self-renewal through activation of the neurotensin / interleukin-8 signaling cascade
- Author
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Yuen Piu Chan, Xin Yuan Guan, Irene Ng, Pak Shing Kwan, Stephanie Ma, Kwok Wah Chan, Kwan Ho Tang, and Terence Lee
- Subjects
MAPK/ERK pathway ,Cancer Research ,medicine.medical_specialty ,Liver tumor ,Oncogene ,Angiogenesis ,Chemistry ,Liver cell ,medicine.disease ,Endocrinology ,Oncology ,Internal medicine ,medicine ,Cancer research ,Signal transduction ,Stem cell ,PI3K/AKT/mTOR pathway - Abstract
A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor, called tumor-initiating cells (TICs). We have previously identified a TIC population from hepatocellular carcinoma (HCC) that is marked by a CD133 surface phenotype and bears features that include the abilities to self-renew, differentiate, initiate tumors in vivo and resist standard chemotherapy through AKT pathway dysregulation (Ma et al., Gastroenterology 2007; Oncogene 2008 and Cell Stem Cell in press). Our present study aims to investigate the underlying molecular mechanism by which CD133+ liver TICs mediate tumor growth and maintenance. cDNA microarray approach was employed to compare gene expression profiles between sorted CD133 subpopulations in HCC cell lines Huh7 and PLC8024. A dysregulated interleukin-8 (IL-8) signaling functional network was preferentially identified in CD133+ liver TICs. IL-8 was found to be overexpressed at both genomic and proteomic (endogenous and secretory) levels in CD133+ cells isolated from HCC cell lines and clinical samples; while its expression also correlated positively with CD133 expression in a panel of liver cell lines. Functional studies on sorted CD133 HCC cells found enhanced IL-8 secretion in CD133+ liver TICs to possess a greater ability to self-renew and induce tumor angiogenesis and growth in vitro and in vivo. These observations were further validated when silencing of IL-8 in CD133+ liver TICs by knockdown or neutralizing antibody approach led to abolishment of these effects. Subsequent studies in the IL-8 functional network also found neurotensin (NTS) and chemokine ligand 1 (CXCL1) to be preferentially expressed in CD133+ liver TICs. Their expression also correlated with that of CD133 and IL-8 across a panel of liver cell lines. Upon addition of exogenous NTS, both expression of IL-8 and CXCL1 was dramatically up-regulated, with concomitant activation of phospho-ERK1/2, a key player of the mitogen-activated protein kinase (MAPK) signaling pathway. Interestingly, enhanced IL-8 secretion in CD133+ liver TICs can in turn activate an IL-8 positive feedback loop through MAPK signaling. Lastly, we also provide evidence to show that the transmembrane protein, CD133, apart from serving as a liver TIC marker, also plays a critical functional role in conferring TIC properties. Stable repression of CD133 in CD133+ liver TICs by lentiviral based approach resulted in inactivation of the NTS / IL-8 / CXCL1 / MAPK signaling cascade and attenuation of TIC self-renewal and tumorigenic properties. Taken together, these results suggest that CD133+ liver TICs promote tumor growth, angiogenesis and self-renewal through activation of NTS / IL-8 signaling cascade. 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 2451. doi:10.1158/1538-7445.AM2011-2451
- Published
- 2011
25. Abstract 2083: microRNA-616 induces androgen-independent growth of prostate cancer cells through suppression of TFPI-2 expression
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Xin Yuan Guan, Juergen R. Vielkind, Yuen Piu Chan, Kwan Ho Tang, Pak Shing Kwan, Stephanie Ma, and Kwok Wah Chan
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PCA3 ,Cancer Research ,Oncogene ,business.industry ,Cancer ,urologic and male genital diseases ,medicine.disease ,Androgen deprivation therapy ,Prostate cancer ,medicine.anatomical_structure ,Oncology ,DU145 ,Prostate ,LNCaP ,Immunology ,Cancer research ,Medicine ,business - Abstract
Prostate cancer is the most frequently diagnosed malignant tumor and the second leading cause of cancer deaths in North America. One of the most troubling aspects of prostate cancer is that, after androgen deprivation therapy, androgen-dependent (AD) prostate cancer inescapably progresses to an androgen-independent (AI) state, for which no effective treatment has been developed. Although several molecular pathways have been suggested to explain the pathogenesis of this disease, to date the mechanisms for the development and progression of prostate cancer remain largely unknown. A better understanding of the molecular events by which AD prostate cancer cells acquire the ability to resist androgen ablation may aid in the development of more effective therapies against this disease. microRNAs (miRNAs) are a class of small, non-coding RNAs that regulate gene expression through the specific targeting of the 3’-untranslated regions (UTRs) of their target mRNAs, thereby inducing degradation of the mRNA itself or impairing its translation. The aim of this project is to examine the differential miRNA profiles in AD and AI prostate cancer. AD LNCaP-FGC and AI LNCaP-LNO, two sublines derived from the same parental prostate cancer cell line LNCaP but bearing different androgen-responsiveness, were analyzed for expression of 419 selected miRNAs. A significant overexpression of miR-616 was identified in AI LNCaP-LNO as well as in malignant prostate tissues than opposed to AD LNCaP-FGC and benign prostate tissues, respectively. Consistently, expression studies of miR-616 in cell lines and xeongrafts representing AD and AI prostate cancer stages, revealed that miR-616 is overexpressed in the more aggressive AI cells (PC3, DU145, C4-2B) when compared with the less aggressive androgen-responsive (AR) cells (22rv1), AD cells (LNCaP, LAPC-4, LAPC-9) or the immortalized, normal prostate cells (HPr-1, NPTx). Stable miR-616 overexpression and knockdown by lentiviral-based approach stimulated and diminished androgen-induced prostate cancer cell proliferation in vitro, respectively. More importantly, inhibition of miR-616 repressed prostate tumor growth in vivo and was sufficient to impart castration resistance as evident by its reduced ability to grow in an in vivo animal model where castration was performed. Subsequent integrated mRNA expression profiling findings (LNCaP-FGC with stable miR-616 overexpression or empty vector) with in silico predictions identified tumor suppressor tissue factor pathway inhibitor-2 (TFPI-2) as a candidate downstream mRNA target of miR-616. Taken together, our results suggest that miR-616 acts as an oncogene, contributing to the pathogenesis of androgen-independent prostate cancer. 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 2083.
- Published
- 2010
26. miR-130b Promotes CD133+ Liver Tumor-Initiating Cell Growth and Self-Renewal via Tumor Protein 53-Induced Nuclear Protein 1.
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Ma, Stephanie, Kwan Ho Tang, Yuen Piu Chan, Lee, Terence K., Pak Shing Kwan, Castilho, Antonia, Ng, Irene, Kwan Man, Wong, Nathalie, Ka-Fai To, Bo-Jian Zheng, Lai, Paul B. S., Chung Mau Lo, Kwok Wah Chan, and Xin-Yuan Guan
- Subjects
TUMORS ,STEM cells ,LIVER cancer ,XENOGRAFTS ,GENE expression ,TUMOR proteins ,NUCLEAR proteins - Abstract
A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor, called tumor-initiating cells (TICs) or cancer stem cells (CSCs). Here we describe the identification and characterization of such cells from hepatocellular carcinoma (HCC) using the marker CD133. CD133 accounts for approximately 1.3%-13.6% of the cells in the bulk tumor of human primary HCC samples. When compared with their CD133
- counterparts, CD133+ cells not only possess the preferential ability to form undifferentiated tumor spheroids in vitro but also express an enhanced level of stem cell-associated genes, have a greater ability to form tumors when implanted orthotopically in immunodeficient mice, and can be serially passaged into secondary animal recipients. Xenografts resemble the original human tumor and maintain a similar percentage of tumorigenic CD133+ cells. Quantitative PCR analysis of 41 separate HCC tissue specimens with follow-up data found that CD133+ tumor cells were frequently detected at low quantities in HCC, and their presence was also associated with worse overall survival and higher recurrence rates. Subsequent differential microRNA expression profiling of CD133+ and CD133- cells from human HCC clinical specimens and cell lines identified an overexpression of miR-130b in CD133+ TICs. Functional studies on miR-130b lentiviral-transduced CD133- cells demonstrated superior resistance to chemotherapeutic agents, enhanced tumorigenicity in vivo, and a greater potential for self renewal. Conversely, antagonizing miR-130b in CD133+ TICs yielded an opposing effect. The increased miR-130b paralleled the reduced TP53INP1, a known miR-130b target. Silencing TP53INP1 in CD133- cells enhanced both self renewal and tumorigenicity in vivo. Collectively, miR-130b regulates CD133+ liver TICs, in part, via silencing TP53INP1. [ABSTRACT FROM AUTHOR]- Published
- 2010
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27. A CD90+ Tumor-Initiating Cell Population with an Aggressive Signature and Metastatic Capacity in Esophageal Cancer.
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Kwan Ho Tang, Yong Dong Dai, Man Tong, Yuen Piu Chan, Pak Shing Kwan, Li Fu, Yan Ru Qin, Sai Wah Tsao, Hong Lok Lung, Lung, Maria L., Tong, Daniel K., Law, Simon, Kwok Wah Chan, Ma, Stephanie, and Xin Yuan Guan
- Subjects
- *
CANCER cells , *ESOPHAGEAL cancer , *TUMOR growth , *LYMPH node diseases , *METASTASIS - Abstract
Tumor-initiating cells (TIC), also known as cancer stem cells, are regarded widely as a specific subpopulation of cells needed for cancer initiation and progression. TICs have yet to be identified in esophageal tumors that have an increasing incidence in developed countries. Here, we report a CD90+ cell population found in esophageal squamous cell carcinoma (ESCC), which is endowed with stem cell--like properties and high tumorigenic and metastatic potential. mRNA profiling of these cells suggested pathways through which they drive tumor growth and metastasis, with deregulation of an Ets-1/MMP signaling pathway and epithelial--mesenchymal transition figuring prominently. These cells possessed higher self-renewal activity and were sufficient for tumor growth, differentiation, metastasis, and chemotherapeutic resistance. CD90+ TICs were isolated and characterized from ESCC clinical specimens as well as ESCC cell lines. In freshly resected clinical specimens, they represented a rare cell population, the levels of which correlated with strong family histories and lymph node metastasis. Our results prompt further study of this CD90+ population of esophageal TICs as potential therapeutic targets. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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28. Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma.
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Man Tong, Kwok Wah Chan, Bao, Jessie Y. J., Kai Yau Wong, Jin-Na Chen, Pak Shing Kwan, Kwan Ho Tang, Li Fu, Yan-Ru Qin, Si Lok, Xin-Yuan Guan, and Ma, Stephanie
- Subjects
- *
TUMOR suppressor genes , *ESOPHAGEAL cancer , *SQUAMOUS cell carcinoma , *DISEASE progression , *BIOMARKERS - Abstract
Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK--Raf--MEK1/2--ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
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