ZIC1 is silenced and has tumor suppressor function in malignant pleural mesothelioma

Yuenyee Cheng, Michaela Kirschner, Nganching Cheng, S Gattani, Sonja Klebe, James Edelman, Michael Vallely, Brian McCaughan, H Jin, Nico van Zandwijk, G Reid

    Research output: Contribution to journalArticlepeer-review

    21 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)1317-1328
    Number of pages12
    JournalJournal of Thoracic Oncology
    Volume8
    Issue number10
    DOIs
    Publication statusPublished - 2013

    Keywords

    • Epigenetic gene silencing
    • Malignant mesothelioma
    • Methylation
    • MiRNA
    • ZIC1

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