OIP5, a target of miR-15b-5p, regulates hepatocellular carcinoma growth and metastasis through the AKT/mTORC1 and β-catenin signaling pathways

Abstract

// Hua Li 1 , Jun Zhang 1 , Mi-Jin Lee 1 , Goung-Ran Yu 1 , Xueji Han 2 , Dae-Ghon Kim 1 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Research Institute of Clinical Medicine, Biomedical Research Institute Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea 2 Department of Infectious Disease, Yanbian University Hospital, Yanji, Jilin Province, China Correspondence to: Dae-Ghon Kim, email: daeghon@chonbuk.ac.kr Keywords: OIP5, miR-15b-5p, hepatocellular carcinoma, tumor growth, metastasis Received: June 29, 2016      Accepted: January 16, 2017      Published: February 08, 2017 ABSTRACT Opa interacting protein 5 (OIP5) is upregulated in some types of human cancers, but the biological implications of its upregulation have not yet been clarified in human hepatocellular carcinoma (HCC). In this study, the signaling pathway downstream of OIP5 was analyzed by proteome kinase profiling. A putative microRNA targeting OIP5 was identified using a miRNA PCR array. Tumorigenicity and metastatic ability were examined in an orthotopic animal model. OIP5 expression was strongly detected in early and advanced tumors via gene expression profiling and immunohistochemical staining analyses. Cells with knockdown of OIP5 via target shRNA exhibited reduced hepatic mass formation and metastatic tumor nodules in an orthotopic mouse model. OIP5-induced AKT activation was mediated by both mTORC2 and p38/PTEN activation. AKT activation was linked to mTORC1 and GSK-3β/β-catenin signaling, which are primarily associated with tumor cell growth and metastasis, respectively. miR-15b-5p, which targets OIP5, efficiently inhibited OIP5-mediated mTORC1 and GSK-3β/β-catenin signaling. These findings suggest that OIP5 may be involved in HCC growth and metastasis and that miR-15b-5p inhibits OIP5-mediated oncogenic signaling in HCC.