microRNA-148a dysregulation discriminates poor prognosis of hepatocellular carcinoma in association with USP4 overexpression
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Mi Jeong Heo1, Young Mi Kim1,2, Ja Hyun Koo1, Yoon Mee Yang1, Jihyun An3, Sook-Kyung Lee4, Seung Jin Lee5, Kang Mo Kim3, Joong-Won Park4 and Sang Geon Kim1
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
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
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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.
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