MicroRNA-31 functions as a tumor suppressor by regulating cell cycle and epithelial-mesenchymal transition regulatory proteins in liver cancer

// Hyung Seok Kim 1,2,* , Kyo Sun Lee 3,* , Hyun Jin Bae 1,2 , Jung Woo Eun 1,2 , Qingyu Shen 1,2 , Se Jin Park 1,2 , Woo Chan Shin 1,2 , Hee Doo Yang 1,2 , Mijung Park 1,2 , Won Sang Park 1,2 , Yong-Koo Kang 3 and Suk Woo Nam 1,2,4 1 Lab of Oncogenomics, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea 2 Functional RNomics Research Center, The Catholic University of Korea, Seoul, Republic of Korea 3 Department of Orthopedic Surgery, College of Medicine, The Catholic University of Korea, Gyeonggi-do, Korea 4 Cancer Evolution Research Center, Catholic University of Korea, Seoul, Republic of Korea * These authors contributed equally to this work Correspondence to: Suk Woo Nam, email: // Keywords : Hepatocellular carcinoma, microRNA-31, CDK2, HDAC2, cell cycle Received : October 01, 2014 Accepted : February 04, 2015 Published : March 10, 2015 Abstract MicroRNA-31 (miR-31) is among the most frequently altered microRNAs in human cancers and altered expression of miR-31 has been detected in a large variety of tumor types, but the functional role of miR-31 still hold both tumor suppressive and oncogenic roles in different tumor types. MiR-31 expression was down-regulated in a large cohort of hepatocellular carcinoma (HCC) patients, and low expression of miR-31 was significantly associated with poor prognosis of HCC patients. Ectopic expression of miR-31 mimics suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. Additional study evidenced miR-31 directly to suppress HDAC2 and CDK2 expression by inhibiting mRNA translation in HCC cells. We also found that ectopic expression of miR-31 mimics reduced metastatic potential of HCC cells by selectively regulating epithelial-mesenchymal transition (EMT) regulatory proteins such as N-cadherin, E-cadherin, vimentin and fibronectin . HCC tissues derived from chemical-induced rat liver cancer models validated that miR-31 expression is significantly down-regulated, and that those cell cycle- and EMT-regulatory proteins are deregulated in rat liver cancer. Overall, we suggest that miR-31 functions as a tumor suppressor by selectively regulating cell cycle and EMT regulatory proteins in human hepatocarcinogenesis providing a novel target for the molecular treatment of liver malignancies.