microRNA-148a dysregulation discriminates poor prognosis of hepatocellular carcinoma in association with USP4 overexpression.

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.

• Authors: Mi Jeong Heo, Young Mi Kim, Ja Hyun Koo, Yoon Mee Yang, Jihyun An, Sook-Kyung Lee, Seung Jin Lee, Kang Mo Kim, Joong-Won Park, Sang Geon Kim
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 9 Pg. 2792-806 (May 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24798342 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GEMIN2 protein, human
• MIRN148 microRNA, human
• MicroRNAs
• Nerve Tissue Proteins
• RNA, Messenger
• RNA-Binding Proteins
• USP4 protein, human
• Ubiquitin Thiolesterase
• Ubiquitin-Specific Proteases

Topics

• Animals
• Apoptosis
• Blotting, Western
• Carcinoma, Hepatocellular (genetics, mortality, pathology)
• Cell Adhesion
• Cell Movement
• Cell Proliferation
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoenzyme Techniques
• Liver Neoplasms (genetics, mortality, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Neoplasm Grading
• Neoplasm Staging
• Nerve Tissue Proteins (genetics, metabolism)
• Prognosis
• RNA, Messenger (genetics)
• RNA-Binding Proteins (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Tumor Cells, Cultured
• Ubiquitin Thiolesterase (genetics, metabolism)
• Ubiquitin-Specific Proteases
• Xenograft Model Antitumor Assays