The emerging roles of non-coding RNAs in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. The development and progression of HCC is a multistep process which attributed to the accumulation of genetic alterations. Recently, mounting evidence has suggested the role of non-coding RNAs (ncRNAs) as the master driver of carcinogenesis, through their regulation on different oncogenes and tumor suppressive genes. Deregulation of ncRNAs was frequently observed in multiple types of cancers, including HCC. Herein, we demonstrated the aberrant expression pattern of miRNAs and lncRNAs in human HCC and investigated their functional roles in promoting hepatocarcinogenesis.

Deregulation of miRNAs was previously demonstrated as a common event in human HCC, and miR-142-3p and miR-142-5pwereidentified as one of the significantly down-regulated miRNAs in HCC. Down-regulation of miR-142-3p and miR-142-5p was frequently observed in HCC patients and their expressions were progressively decreased along the multi-steps HCC development and progression. Functionally, overexpression of miR-142 has significantly inhibited HCC cell migration and invasion. Ectopic expression of miR-142 also markedly attenuated stress fiber formation and disrupted the cytoskeleton organization of HCC cells. Mature miR-142-3p and miR-142-5p, which derived from the same miRNA precursor were shown to collaboratively inhibited HCC cell migration through targeting different components of the key pathways regulating cell motility.

On the other hand, we demonstrated the aberrant expression of lncRNAs in HCC by profiling of 88 well-annotated lncRNAs in 20 pairs of primary HCC and their corresponding non-tumorous liver. HOXA distal transcript antisense RNA (HOTTIP)was identified as the most frequently up-regulated lncRNA in HCC. Functionally, knock down of HOTTIP significantly attenuated cell proliferation in HCC cells and markedly abrogated tumorigenicity in nude mice. Knockdown of HOTTIP had lead to a global reduction in the HOXA genes expression, which are highly expressed in human HCC. Our data suggested that HOTTIP may regulate the expression of its neighboring protein-coding genes and contribute to the development of HCC.

We also investigated the up-stream regulation of HOTTIP and identified miR-125b and miR-29a as regulators of HOTTIP in HCC. Clinically, miR-125b and miR-29a exhibited a reverse expression pattern to HOTTIP in HCC. Ectopic expression of miR-125b and miR-29a abolished HOTTIP-coupled luciferase activity and suppressed the endogenous level of HOTTIP. Intriguingly, we also identified a negative feedback relationship between HOTTIP and miR-125b. Taken together, our findings suggested the up-regulation of HOTTIP may be attributed to the down-regulation of miR-125b and miR-29a in HCC, and the sophisticated regulatory network between HOTTIP and miR-125b has further increased the complexity of gene regulation in HCC.

In conclusion, we demonstrated the dysregulated expression pattern of miRNAs and lncRNAs in HCC and well illustrated their functional roles in promoting hepatocarcinogenesis. From the studies of miR-142 and lncRNA HOTTIP we appreciated the complex interactions and regulations between different ncRNAs. Taken together, our study has enriched the current knowledge on ncRNAs and their involvements in HCC development.