Abstract 600: Maternally expressed gene 3 (MEG3) as a tumor suppressor in nasopharyngeal carcinoma

Abstract

Abstract Nasopharyngeal carcinoma (NPC) is a distinctive type of head and neck cancer arising from the nasopharynx. Although rarely occurring worldwide, the incidence and mortality rates of this tumor are remarkably high among Southern China including Hong Kong. The distinct geographical distribution highlights the significance of several etiologic factors in NPC tumorigenesis, including Epstein-Barr virus (EBV) infection, genetic predisposition and intake of preserved food. However, the understanding of NPC development is still unclear. In our previous genome-wide analysis, chromosome 14q32 has been suggested as a tumor suppressor region where loss of heterozygosity (LOH) was detected in >80% of NPCs. Hence, some novel candidate genes involving in NPC development may be located within this region. By microarray study in NPC samples, consistent down-regulation of a putative tumor suppressor gene, maternally expressed gene 3 (MEG3) within the 14q32 deletion region was identified. MEG3 is an imprinted gene with preferential maternal expression and encodes for a long non-coding RNA. The silenced expression of MEG3 gene in NPC cell lines and xenografts was further confirmed by quantitative RT-PCR. Subsequent DNA methylation analysis in a panel of NPC samples demonstrated that densely methylation at a CpG island on the MEG3 promoter region was observed in all tested NPC cell lines, xenografts and 50% of primary NPCs, while normal imprinting pattern was found in non-cancerous nasopharyngeal epithelium. Interestingly, the presence of demethylation agent in culture medium could successfully rescue MEG3 expression in available NPC cell lines, indicating that promoter hypermethylation is one of the mechanisms to control MEG3 expression. On the other hand, fluorescent in situ hybridization (FISH) also showed the loss of DNA copy number at chromosome 14q32 in 60% of primary NPCs, suggesting an alternative MEG3 regulation mechanism in NPC. In our functional studies, ectopic MEG3 expression in NPC cell lines could significantly inhibit cell propagation, colony and foci formation. A series of reporter assays further suggested that MEG3 might contribute to regulate both p53 and TGF-β signaling pathways. In conclusion, we have found that MEG3 is a novel tumor suppressor gene in NPC. Further investigation the function of MEG3 in NPC pathogenesis may have potential implications to improve NPC treatment in the future. Citation Format: Wing Po Chak, Joanna Hung-Man Tong, Raymond Wai-Ming Lung, Yat Yee Chan, Kwok Wai Lo, Ka Fai To. Maternally expressed gene 3 (MEG3) as a tumor suppressor in nasopharyngeal carcinoma. [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 600. doi:10.1158/1538-7445.AM2014-600