Abstract 3433: Epigenetic silencing of miR-214-3p is associated with resistance to p53-induced apoptosis through up-regulation of gankyrin expression in hepatocellular carcinoma

Abstract

Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and can act as tumor suppressors or oncogenes. To identify miRNA involved in the development of HCC, a genome-wide miRNA gene expression analysis was performed using the human miRNA microarray (Agilent) in paired HCC tumors and non-tumorous liver tissues from patients with primary HCC. The array-based miRNA expression profiles were validated by quantitative PCR. We also screened for genes with promoter DNA hypermethylation using a genome-wide DNA methylation microarray analysis (the Illumina HumanMethylation27 BeadChip) in the same samples. We found that miR-214-3p were significantly down-regulated by aberrant promoter hypermethylation in HCC tumors compared to the non-tumorous liver tissues. We identified PSMD10, which encodes gankyrin, as a direct target of miR-214-3p using luciferase assay and immunoblotting. Gankyrin, an oncoprotein commonly overexpressed in HCC, binds to MDM2, a major E3 ubiquitin ligase for p53, and increases ubiquitylation and degradation of p53. Our experiments showed that reduced miR-214-3p expression was associated with resistance to p53-induced apoptosis through up-regulation of gankyrin expression in HCC cells. In conclusion, our results suggest that epigenetic silencing of tumor suppressor miR-214-3p is involved in hepatocarcinogenesis through up-regulation of gankyrin expression. Citation Format: Kohichiroh Yasui, Naoto Iwai, Kei Terasaki, Yasuyuki Gen, Yoshito Itoh. Epigenetic silencing of miR-214-3p is associated with resistance to p53-induced apoptosis through up-regulation of gankyrin expression in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3433. doi:10.1158/1538-7445.AM2017-3433