The long noncoding RNA HULC promotes liver cancer by increasing the expression of the HMGA2 oncogene via sequestration of the microRNA-186

Abstract

The long noncoding RNA highly up-regulated in liver cancer (HULC) is aberrantly elevated in hepatocellular carcinoma (HCC), and this up-regulation is crucial for HCC pathogenesis. However, the underlying mechanism in HULC up-regulation is poorly understood. We hypothesized that HULC might modulate the oncogene high mobility group A2 (HMGA2) to promote hepatocarcinogenesis. Quantitative real-time PCR analysis showed that the expression levels of HULC were positively correlated with those of HMGA2 in clinical HCC tissues. Interestingly, we also observed that HULC could up-regulate HMGA2 in HCC cells. Mechanistically, we found that the microRNA-186 inhibited HMGA2 expression by targeting the 3-untranslated region (3-UTR) of HMGA2 mRNA. Strikingly, HULC acted as a competing noncoding RNA to sequester miR-186 and thereby relieved miR-186 –mediated HMGA2 repression. Functionally, HMGA2 knockdown decreased the HULC-enhanced growth of HCC cells both in vitro and in vivo. We conclude that the long noncoding RNA HULC increases HMGA2 expression by sequestering miR-186 post-transcriptionally and thereby promotes liver cancer growth, providing new insights into the mechanism by which HULC enhances hepatocarcinogenesis.