Abstract 3551: Dysregulation in microprocessor processing of a primary miRNA, mir-21, leads to downregulation of a tumor suppressor, GHR, progressing hepatocellular carcinoma

Abstract

Improper miRNA biogenesis produces the 5’ variants of miRNA with a shifted seed region (also called isomiRs). Although the presence of stably abundant isomiRs were repeatedly reported, it is still unclear whether the generation of isomiRs results either from the mistake of microprocessor or from the regulation by other intrinsic or extrinsic factors, and whether the isomiRs participate in critical cellular processes, particularly in cancer progress. Here, we performed both high-throughput RNA sequencing (RNA-seq) and small RNA sequencing (sRNA-seq) from 75 hepatocellular carcinoma (HCC) and normal samples (fresh frozen) of Korean HCC cohort. Combined analysis with other publicly available sequencing data, showed that although the expression signatures of isomiRs largely follow those of canonical ones, the relative abundance of some isomiRs are dynamically changed over cancer progression, forming new isomiR-target interactions. Particularly, the biogenesis of highly abundant miR-21 is dysregulated by interaction with HNRNPC to primary mir-21 during cancer progress, producing relatively more isomiR-21-5p in HCC. Introducing isomiR-21-5p mimic or antagomir against isomiR-21-5p, and the dysregulation of HNRNPC expression perturbed the relative abundance of isomiR-21-5p, leading to dysregulation of miRNA targeting on a tumor suppressor gene, GHR, and affecting cancer progress. Our study not only describes that isomiR-21-5p is an independent prognostic marker and a potential therapeutic target of HCC but also presents that the production of isomiRs is tightly regulated by other extrinsic factors in cells. Citation Format: Seokju Park, Hee Doo Yang, Jwawon Seo, Seokwoo Nam, Jin-Wu Nam. Dysregulation in microprocessor processing of a primary miRNA, mir-21, leads to downregulation of a tumor suppressor, GHR, progressing hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3551.