S1P receptor‐1 and USP4 induced by microRNA‐148a deregulation facilitate liver cancer progression (766.1)

Abstract

Hepatocellular carcinoma (HCC) is frequently aggressive. MicroRNAs (miRNAs) emerge as key contributors to tumor progression. In the present study, we report that deregulation of miR‐148a causes the induction of sphingosine 1‐phosphate receptor 1 (S1P1) and ubiquitin specific protease 4 (USP4) in association with HCC progression. In patients with HCC, S1P1 and USP4 were both up‐regulated with miR‐148a deregulation. Moreover, decrease of miR‐148a discriminated microvascular invasion of HCC, the overall survival and recurrence free survival rates of the patients. In cell models, miR‐148a was repressed in mesenchymal‐typed liver‐tumor cells, which facilitated S1P1 and USP4 induction, as shown by the assays using mimic, antisense oligonucleotide and 3’‐UTR reporter. S1P1 and USP4 levels were markedly increased in liver‐tumor cells having a mesenchymal phenotype. S1P1 over‐expression enhanced ERK1/2 activation, increasing proliferation and migration of liver‐tumor cells, which was attenuated by miR‐148a mimic transfection. Decrease of miR‐148a additionally caused USP4 induction, which may account for TGFβ1‐dependent epithelial‐mesenchymal transition (EMT) in HCC. In summary, S1P1 and USP4 induced by miR‐148a deregulation may facilitate HCC growth and migration in microenvironments, and contribute to cancer progression.