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.
Highlights
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
We conclude that HULC is positively correlated with high mobility group A2 (HMGA2) in clinical HCC tissues and up-regulates HMGA2 in HCC cells
Given that long ncRNAs (lncRNAs) can act as an miRNA sponge to promote the development of cancers [30, 36], we presumed that HULC might contribute to the elevation of HMGA2 by sequestering miRNAs
Summary
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. Up-regulated in liver cancer (HULC) was identified as the overexpressed long noncoding RNA in hepatocellular carcinoma (HCC) [6]. MiRNAs act as post-transcriptional regulators of gene expression through directly binding to the 3Ј-UTR of the target mRNAs [14]. It has been reported that HMGA2 is inhibited by let-7 in breast cancer and miR-107 in HCC [22, 27] It can be increased by the Wnt/-catenin pathway [28]. Our data showed that HULC increases HMGA2 expression by sequestering miR-186 post-transcriptionally and thereby promotes liver cancer growth. Our finding provides new insights into the mechanism of hepatocarcinogenesis mediated by lncRNA HULC
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