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.
Highlights
Hepatocellular carcinoma (HCC) belongs to common and aggressive human malignancies and is one of the leading causes of death by tumor worldwide
Our results demonstrate that overexpression of ubiquitin specific protease 4 (USP4) and sphingosine 1-phosphate receptor 1 (S1P1) due to miR-148a dysregulation contributes to the growth advantage or migrating capability of liver tumor
Our findings showed for the first time that the overall survival, and the recurrence free survival rates of HCC patients were discerned by the level of miR-148a
Summary
Hepatocellular carcinoma (HCC) belongs to common and aggressive human malignancies and is one of the leading causes of death by tumor worldwide. MiRNAs emerge as key contributors to tumor progression because of the ability to control multiple targets and alter biological functions [3]. Due to their stability, miRNAs are considered as useful tumor biomarkers [4]. MiR-148a belongs to abundant miRNAs in hepatocytes, and is severely deregulated in several tumors including HCC [5,6]. It has been shown that several forms of USP (e.g., 4, 11 and 15) enhance transforming growth factor-β (TGF-β) signaling, which facilitates tumor cell invasion, migration, and aggressiveness [8,9]. The contribution of USP to HCC progression has not been determined
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