The Role of Long Non-Coding RNAs in Hepatocarcinogenesis

Abstract

Whole-transcriptome analyses have revealed that a large proportion of the human genome is transcribed in non-protein-coding transcripts, designated as long non-coding RNAs (lncRNAs). Rather than being "transcriptional noise", increasing evidence indicates that lncRNAs are key players in the regulation of many biological processes, including transcription, post-translational modification and inhibition and chromatin remodeling. Indeed, lncRNAs are widely dysregulated in human cancers, including hepatocellular carcinoma (HCC). Functional studies are beginning to provide insights into the role of oncogenic and tumor suppressive lncRNAs in the regulation of cell proliferation and motility, as well as oncogenic and metastatic potential in HCC. A better understanding of the molecular mechanisms and the complex network of interactions in which lncRNAs are involved could reveal novel diagnostic and prognostic biomarkers. Crucially, it may provide novel therapeutic opportunities to add to the currently limited number of therapeutic options for HCC patients. In this review, we summarize the current status of the field, with a focus on the best characterized dysregulated lncRNAs in HCC.

Keywords: carcinogenesis; hepatocellular carcinoma; liver cancer; long non-coding RNA.

Figure 1

Long non-coding RNA (LncRNA) classification in the context of different genomic locations. On the basis of genomic location and orientation to genes there are four major classes of lncRNAs. (a) Antisense lncRNAs are transcribed from the opposite strand of coding genes; (b) Bidirectional lncRNAs are transcribed from the opposite strand, in the opposite direction and within 1 kb of the promoter of coding genes; (c) Intergenic lncRNAs are transcribed in the genomic region between two coding genes and usually are located in enhancer regions acting in cis on the promoters of the downstream genes; and, (d) Sense-intronic lncRNAs are transcribed from the sense strand of an intronic region with no overlap of exonic sequence. Ex: exon.

Figure 2

Mechanism of function of lncRNAs dysregulated in hepatocellular carcinoma (HCC). LncRNAs may act as sponges for miRNAs, bind transcripts or proteins and induce epigenetic modifications or chromatin remodeling. Their deregulation leads to hepatocellular carcinogenesis by regulating different cellular processes such as migration, proliferation, invasion, cell cycle, apoptosis and epithelial mesenchymal transition (EMT). Examples of the mechanisms of action of lncRNAs dysregulated in HCC are reported. See text for details.

Figure 3

Diagnostic/prognostic and therapeutic potentials of lncRNAs. LncRNAs isolated from liquid biopsies or tissues could be analyzed at the sequence or expression levels and may serve as potential biomarkers for HCC diagnosis, prognosis and therapy response prediction. LncRNAs may also be targeted for therapeutic interventions by silencing their expression using canonical Argonaute2 mediated interference (siRNA) molecules or antisense oligonucleotides (ASO), by blocking the interactions with DNA, RNA, or proteins using small synthetic molecules or by CRISPR/Cas9 editing.