Roles and Regulation of Long Noncoding RNAs in Hepatocellular Carcinoma.

Lee Jin Lim,Caroline G Lee,Samuel S Chong,London Lucien Ooi,Sheng Lim,Feiyang Huang,Samuel Y.S Wong,Oi Lian Kon

doi:10.1158/0008-5472.can-19-0255

Abstract

Next-generation sequencing has uncovered thousands of long noncoding RNAs (lncRNA). Many are reported to be aberrantly expressed in various cancers, including hepatocellular carcinoma (HCC), and play key roles in tumorigenesis. This review provides an in-depth discussion of the oncogenic mechanisms reported to be associated with deregulated HCC-associated lncRNAs. Transcriptional expression of lncRNAs in HCC is modulated through transcription factors, or epigenetically by aberrant histone acetylation or DNA methylation, and posttranscriptionally by lncRNA transcript stability modulated by miRNAs and RNA-binding proteins. Seventy-four deregulated lncRNAs have been identified in HCC, of which, 52 are upregulated. This review maps the oncogenic roles of these deregulated lncRNAs by integrating diverse datasets including clinicopathologic features, affected cancer phenotypes, associated miRNA and/or protein-interacting partners as well as modulated gene/protein expression. Notably, 63 deregulated lncRNAs are significantly associated with clinicopathologic features of HCC. Twenty-three deregulated lncRNAs associated with both tumor and metastatic clinical features were also tumorigenic and prometastatic in experimental models of HCC, and eight of these mapped to known cancer pathways. Fifty-two upregulated lncRNAs exhibit oncogenic properties and are associated with prominent hallmarks of cancer, whereas 22 downregulated lncRNAs have tumor-suppressive properties. Aberrantly expressed lncRNAs in HCC exert pleiotropic effects on miRNAs, mRNAs, and proteins. They affect multiple cancer phenotypes by altering miRNA and mRNA expression and stability, as well as through effects on protein expression, degradation, structure, or interactions with transcriptional regulators. Hence, these insights reveal novel lncRNAs as potential biomarkers and may enable the design of precision therapy for HCC.

Highlights

As the sixth most common and fourth most fatal cancer in the world [1], hepatocellular carcinoma (HCC) is a major global health problem
By integrating diverse datasets, including clinicopathologic associations, cancer phenotypes, miRNA- and protein-interacting partners, altered transcriptomes, and protein expression, this review attempts to provide a perspective of 74 long noncoding RNAs (lncRNA) known to be deregulated in HCC, with an emphasis on integrating their oncogenic functions into a coherent model
Deregulated lncRNA expression is pervasive across many cancers, including HCC

Summary

Introduction

As the sixth most common and fourth most fatal cancer in the world [1], hepatocellular carcinoma (HCC) is a major global health problem. The HBx-LINE1 fusion transcript is an lncRNA that activates Wnt signaling, promotes HCC development and progression, and correlates with shorter patient survival [50]. These observations point to the considerable potential of lncRNAs as a source of novel targetable molecules for HCC precision therapy and for discovering new diagnostic biomarkers. By integrating diverse datasets, including clinicopathologic associations, cancer phenotypes, miRNA- and protein-interacting partners, altered transcriptomes, and protein expression, this review attempts to provide a perspective of 74 lncRNAs known to be deregulated in HCC, with an emphasis on integrating their oncogenic functions into a coherent model. MEG3 expression in normal hepatocytes and HCC is correlated with expression of miR-29, which directly blocks DNMT mRNA

Post-transcriptional level – miRNA and RNA binding proteins

Findings

Conclusion and Future Perspectives