• Yuen Yee Cheng, Michaela B Kirschner, Ngan Ching Cheng, Sumedha Gattani, Sonja Klebe, J James B Edelman, Michael P Vallely, Brian C McCaughan, Hong Chuan Jin, Nico van Zandwijk, and Glen Reid.
• *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.
• J Thorac Oncol. 2013 Oct 1; 8 (10): 1317-28.

IntroductionEpigenetic 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.MethodsZIC1 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.ResultsZIC1 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.ConclusionZIC1 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.

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