MiR-483-5p promotes IGF-II transcription and is associated with poor prognosis of hepatocellular carcinoma

Abstract

// Shaohui Tang 1, * , Yanfang Chen 1, * , Shufen Feng 1, * , Tingzhuang Yi 2, * , Xuyou Liu 3, * , Qiang Li 4 , Zhilong Liu 4 , Cuiping Zhu 1 , Jianjun Hu 1 , Xi Yu 1 , Min Wang 1 , Guoli Cao 1 , Hui Tang 5 , Caiqun Bie 6 , Feng Ma 1 , Huijun Tang 6 , Gang Du 5 and Jianwei Huang 3 1 Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China 2 Department of Gastroenterology, Affiliated Hospital of Youjiang Medical University for Nationlities, Baise, Guangxi, China 3 Department of Gastroenterology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China 4 Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China 5 Clinical Medicine Research Institute, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China 6 Department of Gastroenterology, The Affiliated Shenzhen Shajing Hospital, Guangzhou Medical University, Shenzhen, Guangdong, China * These authors contributed equally to this work Correspondence to: Jianwei Huang, email: dthjw2007@aliyun.com Shaohui Tang, email: tangshaohui206@163.com Keywords: miRNAs, transcription regulation, ago proteins, liver cancer, inferior clinical outcome Received: August 01, 2017      Accepted: September 22, 2017      Published: October 11, 2017 ABSTRACT The human insulin-like growth factor-II (IGF-II) gene transcribes four mRNAs (P1 mRNA-P4 mRNA), and P3 mRNA overexpression contributes to hepatocarcinogenesis. IGF-II-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in P3 mRNA overexpression regulation and its role in hepatocellular carcinoma. Our results showed that miR-483-5p up-regulated P3 mRNA transcription by targeting the 5′-untranslated region (5′UTR) of P3 mRNA in hepatocellular carcinoma. The mechanism was involved in recruiting of an argonaute 1(Ago1)-argonaute 2 (Ago2) complex to the P3 mRNA 5′UTR and the P3 promoter of IGF-II gene by miR-483-5p, accompanied by increased enrichment of RNA polymerase II and activating histone marks histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 27 acetylation (H3K27ac), and histone 4 lysine 5/8/12/16 acetylation (H4Kac) at the P3 promoter. High miR-483-5p expression was an independent predictor for shorter survival of HCC patients. The findings suggest that miR-483-5p promotes P3 mRNA transcription by recruiting the Ago1-Ago2 complex to the P3 mRNA 5′UTR and is associated with poor prognosis of HCC. Our results display a potential new model for miRNAs to up-regulate gene expression.