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ZIC1 is silenced and has tumor suppressor function in malignant pleural mesothelioma
Yuen Yee Cheng1, Michaela B Kirschner, Ngan Ching Cheng
1*Asbestos Diseases Research Institute, University of Sydney, Sydney, Australia; †Department of Anatomical Pathology, Flinders Medical Centre, Adelaide, Australia; ‡Cardiothoracic Surgical Unit, Royal Prince Alfred Hospital; The Baird Institute, Sydney Medical School, University of Sydney, Sydney, Australia; and §Biomedical Research Center, Sir Runrun Shaw Hospital, Zhejiang University, Hangzhou, China.
Introduction:
Epigenetic inactivation of tumor suppressor genes is involved in the development of malignant pleural mesothelioma (MPM). ZIC1, a potential tumor suppressor gene involved in regulating cell growth and apoptosis, was investigated in MPM cell lines and tumors.
Methods:
ZIC1 expression and promoter methylation were evaluated in MPM cell lines and tumor samples by quantitative polymerase chain reaction (PCR), Combined Bisulfite Restriction Analysis, and methylation-specific PCR. ZIC1 was reexpressed in cell lines and functional effects were assessed. miRNA expression was quantified by microarray and reverse transcription quantitative PCR. ZIC1 knockdown and miRNA inhibitors were used to study the relationship between ZIC1 and miRNA expression and confirmed by chromatin immunoprecipitation PCR.
Results:
ZIC1 expression was low in MPM cells, and was correlated with ZIC1 promoter methylation and reversed upon decitabine treatment. ZIC1 reexpression inhibited proliferation and invasion in MPM cells whereas knockdown enhanced the growth of MeT-5A. In MPM tumor samples ZIC1 expression was either low or undetectable, with promoter methylation observed in 16 of 24 cases. The overexpression of miR-23a and miR-27a was reduced by ZIC1 reexpression, with inhibitors of miR-23a or miR-27a reducing colony formation. miR-23a overexpression was also associated with shorter survival of MPM patients.
Conclusion:
ZIC1 is down-regulated in MPM through promoter methylation and acts as a tumor suppressor through down-regulation of its direct targets miR-23a and miR-27a.
Insights
ZIC1 is a tumor suppressor gene silenced by methylation in malignant pleural mesothelioma (MPM). Restoring ZIC1 inhibits MPM cell growth and invasion by downregulating miR-23a and miR-27a.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Malignant pleural mesothelioma (MPM) development involves epigenetic silencing of tumor suppressor genes.
- ZIC1, a potential tumor suppressor regulating cell growth and apoptosis, was studied in MPM.
Purpose of the Study:
- To investigate the role of ZIC1 in MPM.
- To determine the mechanisms of ZIC1 regulation and its functional impact in MPM.
Main Methods:
- Quantitative PCR, Combined Bisulfite Restriction Analysis, and methylation-specific PCR were used to assess ZIC1 expression and promoter methylation.
- ZIC1 reexpression and knockdown experiments were performed in MPM cell lines.
- Microarray and RT-qPCR were used to quantify miRNA expression; ZIC1 and miRNA interactions were confirmed via ChIP-PCR.
Main Results:
- ZIC1 expression was low in MPM cells and tumors, correlating with promoter methylation.
- ZIC1 reexpression suppressed MPM cell proliferation and invasion; ZIC1 knockdown enhanced MeT-5A cell growth.
- ZIC1 reexpression reduced miR-23a and miR-27a overexpression; miR-23a overexpression correlated with shorter patient survival.
Conclusions:
- ZIC1 acts as a tumor suppressor in MPM, downregulated by promoter methylation.
- ZIC1 exerts its tumor-suppressive function by downregulating its direct targets, miR-23a and miR-27a.
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