Long non-coding RNA AOC4P suppresses hepatocellular carcinoma metastasis by enhancing vimentin degradation and inhibiting epithelial-mesenchymal transition

// Tong-Hong Wang 1 , Yong-Shiang Lin 2 , Ying Chen 1 , Chau-Ting Yeh 3 , Yen-lin Huang 2 , Tsung-Han Hsieh 1 , Tzong-Ming Shieh 4 , Chuen Hsueh 1, 2 , Tse-Ching Chen 1, 2 1 Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan 2 Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan 3 Department of Hepato-Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan 4 Department of Dental Hygiene, College of Health Care, China Medical University, Taichung, Taiwan Correspondence to: Chuen-Hsueh, e-mail: ch9211@adm.cgmh.org.tw Tse-Ching Chen, e-mail: ctc323@adm.cgmh.org.tw Keywords: long non-coding RNA (lncRNA), hepatocellular carcinoma (HCC), epithelial-mesenchymal transition (EMT), metastasis Received: April 09, 2015      Accepted: June 12, 2015      Published: June 23, 2015 ABSTRACT Increasing evidence indicates that long non-coding RNAs (lncRNAs) regulate diverse cellular processes, including cell growth, differentiation, apoptosis, and cancer progression. However, the function of lncRNAs in the progression of hepatocellular carcinoma (HCC) remains largely unknown. We performed a comprehensive microarray analysis of lncRNA expression in human HCC samples. After validation in 108 HCC specimens, we identified a differentially expressed novel tumor suppressive lncRNA termed amine oxidase, copper containing 4, pseudogene (AOC4P). The level of AOC4P expression was significantly downregulated in 68% of HCC samples and negatively correlated with advanced clinical stage, capsule invasion and vessel invasion. Low AOC4P expression correlated with poor prognostic outcomes, serving as an independent prognostic factor for HCC. In vitro functional assays indicated that AOC4P overexpression significantly reduced cell proliferation, migration and invasion by inhibiting the epithelial-mesenchymal transition (EMT). RNA immunoprecipitation assays demonstrated that AOC4P binds to vimentin and promotes its degradation. Animal model experiments confirmed the ability of AOC4P to suppress tumor growth and metastasis. Taken together, our findings suggest that AOC4P lncRNA acts as an HCC tumor suppressor by enhancing vimentin degradation and suppressing the EMT. By clarifying the mechanisms underlying HCC progression, these findings promote the development of novel therapeutic strategies for HCC.