Abstract LB-352: Functional significance of Zic1 and hsa-miR-23a over-expression in malignant mesothelioma

Abstract

Abstract Background: Epigenetic inactivation of tumour suppressor genes plays a crucial role in the progression of malignant mesothelioma (MM). Previous research has shown epigenetic gene silencing, through DNA methylation or through control of mRNA expression by microRNAs, to be important in MM. Our previous work indicated that Zic1 silencing in MM lines is only partially explained through DNA hypermethylation. Interestingly, miRNA microarray analysis revealed that hsa-miR-23a is over-expressed in MM cell lines, and that this miRNA has target sites in the 3′UTR of the Zic1 mRNA. The aim of the current study was to investigate the functional significance of Zic1 silencing and hsa-miR-23a over-expression in MM. Methods: We first confirmed DNA hypermethylation of Zic1 in human MM specimens using MSP, MS-HRM and COBRA. The expression level of hsa-miR-23a was also confirmed in MM using qPCR. To investigate the functional significance of Zic1 silencing, Zic1 was re-expressed in MM cell lines and effects on proliferation, migration and growth in soft agar were assessed. The relationship between hsa-miR-23a and Zic1 expression was investigated by the use of an antagonist of hsa-miR-23a. Results: Our results indicated that Zic1 is hypermethylated and ectopic expression of Zic1 inhibited cell migration and cell proliferation in MM cell lines. Hsa-miR-23a overexpression in MM is closely linked to the expression of Zic1. Our results suggest that Zic1 is a functional tumour suppressor gene that is silenced by a combination of hypermethylation and hsa-miR-23a-mediated inhibition in MM. These findings suggest that hsa-miR-23a is a potential therapeutic target for MM deserving further pre-clinical study. 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 LB-352. doi:10.1158/1538-7445.AM2011-LB-352