Abstract 958: MiR-196b is an epigenetically silenced tumor suppressor for lung cancer

Silencing of microRNAs by promoter hypermethylation could play a significant role in lung cancer initiation and progression. A pre-malignancy model using carcinogen transformed human bronchial epithelial cells (HBECs) treated with the demethylating agent 5-aza-2’deoxycytidine followed by next-generation sequencing identified miR-196b and miR-34c-5p as being epigenetically regulated. Bisulfite sequencing confirmed silencing via dense promoter hypermethylation that was commonly replicated in malignant cell lines and primary tumors. Functional studies of miR-196b revealed that it was epigenetically silenced by chromatin modification and DNA methylation during transformation of HBECs and re-expression modulated genes involved in cell cycle regulation. Stable re-expression led to a cell cycle arrest mediated in part through transcriptional regulation of the FOS oncogene that was replicated in vivo by a profound reduction in growth of tumor xenografts. Luciferase assays demonstrated that forced expression of miR-196b inhibits FOS promoter and AP-1 reporter activity. A case-control study showed that methylation of miR-196b in sputum was strongly associated with lung cancer (OR = 4.7, p Citation Format: Carmen S. Tellez, Daniel E. Juri, Kieu Do, Maria A. Picchi, Teresa Wang, Gang Liu, Avrum Spira, Steven A. Belinsky. MiR-196b is an epigenetically silenced tumor suppressor for lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 958.