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Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications

Key Points

  • Protein-coding sequence accounts for only 2% of the human genome, with the function of the remaining 98% of non-coding sequences in the human genome being largely elusive

  • A large number of small and long non-coding RNAs (ncRNAs) have been identified, and deregulation of ncRNAs has a critical role in liver carcinogenesis

  • MicroRNAs negatively regulate gene expression at the post-transcriptional level; microRNAs can function as an 'oncomiRs' to repress tumour-suppressor genes or, vice versa, can act as a tumour suppressor to counteract oncogenes

  • Long ncRNAs belong to functionally divergent groups of ncRNAs that regulate gene expression and other molecular functions through interacting with DNA, RNA and proteins

  • Deregulation of ncRNAs profoundly contributes to liver carcinogenesis of diverse aetiologies, liver cancer stem cell formation, hepatocellular carcinoma epigenetic reprogramming and cancer metastasis

  • Non-coding RNAs are potential molecular markers and therapeutic targets of human hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a leading lethal malignancy worldwide. However, the molecular mechanisms underlying liver carcinogenesis remain poorly understood. Over the past two decades, overwhelming evidence has demonstrated the regulatory roles of different classes of non-coding RNAs (ncRNAs) in liver carcinogenesis related to a number of aetiologies, including HBV, HCV and NAFLD. Among the ncRNAs, microRNAs, which belong to a distinct class of small ncRNAs, have been proven to play a crucial role in the post-transcriptional regulation of gene expression. Deregulation of microRNAs has been broadly implicated in the inactivation of tumour-suppressor genes and activation of oncogenes in HCC. Modern high-throughput sequencing analyses have unprecedentedly identified a very large number of non-coding transcripts. Divergent groups of long ncRNAs have been implicated in liver carcinogenesis through interactions with DNA, RNA or proteins. Overall, ncRNAs represent a burgeoning field of cancer research, and we are only beginning to understand the importance and complicity of the ncRNAs in liver carcinogenesis. In this Review, we summarize the common deregulation of small and long ncRNAs in human HCC. We also comprehensively review the pathological roles of ncRNAs in liver carcinogenesis, epithelial-to-mesenchymal transition and HCC metastasis and discuss the potential applications of ncRNAs as diagnostic tools and therapeutic targets in human HCC.

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Figure 1: Milestones of non-coding RNA discovery and their roles in hepatocellular carcinoma.
Figure 2: Mechanisms and functions of small non-coding RNAs.
Figure 3: Classification of long non-coding RNAs according to their genomic origin.
Figure 4: Diverse molecular mechanisms of long non-coding RNAs.

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Acknowledgements

The study was supported by the Hong Kong Research Grants Council Theme-based Research Scheme (T12-704/16R), the Hong Kong Health and Medical Research Fund (03142996 and 04150776), the S.K. Yee Medical Research Foundation (2011), the University Development Fund of The University of Hong Kong and the Hong Kong Innovation and Technology Commission Fund. I.O.-L.N. is the Loke Yew Professor in Pathology.

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Contributions

C.-M.W. and F.H.-C.T. researched data for the article. C.-M.W., F.H.-C.T. and I.O.-L.N. wrote the Review. C.-M.W. and I.O.-L.N. reviewed and edited the article.

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Correspondence to Irene Oi-Lin Ng.

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Supplementary information

Supplementary Table 1

Oncogenic small non-coding RNAs upregulated in HCC (PDF 135 kb)

Supplementary Table 2

Tumour suppressive small non-coding RNAs downregulated in HCC (PDF 170 kb)

Supplementary Table 3

Oncogenic long non-coding RNAs in HCC (PDF 196 kb)

Supplementary Table 4

Tumor suppressive long non-coding RNAs in HCC (PDF 144 kb)

PowerPoint slides

Glossary

Non-coding RNAs

(ncRNAs). RNA transcripts that do not code for protein. ncRNAs can be broadly divided into small ncRNAs and long ncRNAs on the basis of an arbitrary cut-off length of 200 nucleotides. Many ncRNAs play regulatory roles in gene expression and other molecular functions.

3′ untranslated region

(3′UTR). The mRNA sequence after the stop codon. It is a regulatory element and is frequently targeted by microRNA to negatively regulate gene expression.

Seed sequence

The 5′ sequence of a mature microRNA usually at position 2–8. The seed sequence governs the specificity of microRNA–mRNA interaction via complementary binding.

Liver cancer stem cells

(LCSCs). A small subset of cancer cells present within a hepatocellular carcinoma (HCC) tumour that possess self-renewal capability and are implicated in HCC tumour initiation, cancer metastasis and drug resistance. They are characterized by specific surface markers, including CD133, CD13, CD24 and epithelial cell adhesion molecule (EPCAM).

Epithelial–mesenchymal transition

(EMT). A cellular process by which cancer cells lose their epithelial cell features and become more mesenchymal. EMT is known to be important for cancer metastasis.

Polycomb group complex 2

(PRC2). An epigenetic regulator consisting of histone–lysine N-methyltransferase (EZH2) and Polycomb proteins EED and SUZ12. PCR2 is responsible for installing histone 3 lysine 27 trimethylation at a gene promoter to repress the corresponding gene expression.

Competitive endogenous RNAs

(ceRNAs). Endogenous transcripts (mRNA or non-coding RNAs) that function as a molecular sponge to regulate the expression of other RNAs through competing for the binding of shared regulatory microRNA(s).

Post-transcriptional regulation

Mechanisms that regulate gene expression after mRNA transcription, usually through controlling RNA stability or protein translation.

Passenger strand

(miR*). A minor form of a microRNA (miRNA) duplex generated by the processing of precursor miRNA by the endoribonuclease Dicer. The other strand — guide stand miRNA — is the major form and is functionally active, mature miRNA. Strand selection in miRNA processing is dependent on the thermodynamic feature of the miRNA duplex, and the passenger stand will normally be degraded. Nevertheless, in some cases the passenger strand is also abundantly expressed and might have activity to regulate post-transcriptional gene expression. Guide strand miRNA and passenger strand miRNA have different seed sequences and target different mRNA populations.

Nanoliposome-incorporated miRNA

A microRNA (miRNA) mimic that is enclosed in liposome (phospholipid) nanoparticle to form a micelle-like structure. The nanoliposome serves as an miRNA carrier to improve the stability in circulation and enhance entry.

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Wong, CM., Tsang, FC. & Ng, IL. Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications. Nat Rev Gastroenterol Hepatol 15, 137–151 (2018). https://doi.org/10.1038/nrgastro.2017.169

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