// Mi Jeong Heo 1 , Young Mi Kim 1,2 , Ja Hyun Koo 1 , Yoon Mee Yang 1 , Jihyun An 3 , Sook-Kyung Lee 4 , Seung Jin Lee 5 , Kang Mo Kim 3 , Joong-Won Park 4 and Sang Geon Kim 1 1 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea; 2 College of Pharmacy, Hanyang University, Ansan, Gyeonggido, Korea; 3 Department of Internal Medicine, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 4 Center for Liver Cancer, National Cancer Center, Goyang, Korea; 5 College of Pharmacy, Gachon University, Incheon, Korea Correspondence: Sang Geon Kim, email: // Keywords : hepatocellular carcinoma; USP4; S1P1; miR-148a; migration; growth Received : February 23, 2014 Accepted : April 24, 2014 Published : April 25, 2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Hepatocellular carcinoma (HCC) is classified as a poor prognostic tumor, and becomes frequently aggressive. MicroRNAs emerge as key contributors to tumor progression. This study investigated whether miR-148a dysregulation differentiates poor prognosis of HCC, exploring new targets of miR-148a. miR-148a dysregulation discriminated not only the overall survival and recurrence free survival rates of HCC, but the microvascular invasion. In the human HCC samples, ubiquitin specific protease 4 (USP4) and sphingosine 1-phosphate receptor 1 (S1P1) were up-regulated as the new targets of miR-148a. USP4 and S1P1 were up-regulated in mesenchymal-type liver-tumor cells with miR-148a dysregulation, facilitating migration and proliferation of tumor cells. The inverse relationship between miR-148a and the identified targets was verified in a tumor xenograft model. In the analysis of human samples, the expression of USP4, but not S1P1, correlated with the decrease of miR-148a. In a heterotropic patient-derived HCC xenograft model, USP4 was also overexpressed in G1 and G2 tumors when miR-148a was dysregulated, reflecting the closer link between miR-148a and USP4 for a shift in the expansion phase of tumorgraft. In conclusion, miR-148a dysregulation affects the poor prognosis of HCC. Of the identified targets of miR-148a, USP4 overexpression may contribute to HCC progression towards more aggressive feature.
