Long noncoding RNA network: Novel insight into hepatocellular carcinoma metastasis (Review)

Abstract

Hepatocellular carcinoma (HCC) is one of the most common, aggressive malignancies with poor prognosis and high mortality. Although great progress has been made in recent decades, overall survival of HCC patients remains unsatisfactory due to high recurrence and metastasis. Accordingly, understanding and clarifying the underlying molecular mechanisms of metastasis has become increasingly important. Recently, accumulated reports have supported that long noncoding RNAs (lncRNAs) are dysregulated in HCC and are involved in various pivotal biological processes, including metastasis. The aim of this review was to investigate the dysregulation of lncRNAs in HCC and their function as oncogenes or tumour suppressors. Furthermore, reciprocal regulatory networks between lncRNAs and various molecules that were identified in HCC metastasis, including regulating epithelial‑mesenchymal transition (EMT), controlling metastasis‑associated genes, and regulating tumour angiogenesis were examined. Numerous reports and information on lncRNAs may help identify lncRNAs that are potential novel diagnostic markers, prognostic markers and therapeutic targets.

Keywords: epithelial‑mesenchymal transition; hepatocellular carcinoma; long noncoding RNA; metastasis; therapeutic targets.

Figure 1

lncRNAs are aberrantly expressed in HCC. (A) HULC, which is upregulated in HCC, promotes tumorigenesis by controlling some pathways, such as upregulation of HMGA2, promotion of EMT via miR-200a-3p, promotion of abnormal lipid metabolism via RXRA and upregulation of SPHK1 to promote tumour angiogenesis. (B) MEG3, which is downregulated in HCC, inhibits tumorigenesis by regulating some pathways, such as the MEG3/miR-664/ADH4 and DNMT1/MEG3/P53 signalling axes. HCC, hepatocellular carcinoma; HULC, highly upregulated in liver cancer.

Figure 2

lncRNAs regulating EMT transcription factors and direct targets. A schematic model and regulatory network of lncRNA functions during the process of EMT are summarized. SNAIL1/2 and ZEB1/2 are EMT-related transcription factors, and E-cadherin, Vimentin and N-cadherin are direct EMT targets. Dysregulation of lncRNAs may lead to EMT progression by affecting EMT transcription factors or direct targets. For example, lncRNA-ATB and lncRNA HULC upregulated ZEB1/2 expression by competitively binding miR-200a, whereas lncRNA CCAT2 promoted SNAIL2 and ZEB1 expression, and decreased the expression of E-cadherin, leading to EMT.

Figure 3

lncRNA-mediated control of EMT signalling pathways. Schematic representation of lncRNAs that are deregulated in human hepatocellular carcinoma-mediated control of EMT signalling pathways. TGF-β, Wnt/β-catenin, PI3K, and Notch signalling pathways affected by the upregulated lncRNAs ATB, MALAT1, lncRNA MUF, BC087858 and HOTAIR or the downregulated lncRNAs P21 and CPS1-IT1 may lead to EMT progression.

Figure 4

A schematic model and regulatory network of lncRNAs promoting HCC invasion and metastasis. The HOTAIR/PRC2/H3K27me3/HOXD, HOXD-AS1/miR-130a-3p/SOX4/EZH2, MMP2 and HOXD-AS1/miR-19a/ARHGAP11A signalling pathways form a cascade effect for HCC metastasis.

Figure 5

A schematic model of MALAT promoting HCC metastasis by targeting multiple genes. lncRNAs MALAT1 and EZH2 or HIF-2α, as upstream regulators, and their downstream targets, including EGFR, ZEB1, LEBP3 and TRAF6, compose a delicate network to regulate HCC metastasis.

Figure 6

A schematic model of lncRNAs dysregulated in HCC affecting HCC angiogenesis by regulating VEGF or HIF-1A. Aberrantly expressed lncRNAs may affect cancer-associated angiogenesis. For example, upregulation of HOTAIR promoted tumour angiogenesis by directly activating VEGFA and Ang2 expression.