The role of RNA binding proteins in hepatocellular carcinoma
Graphical abstract
Introduction
Hepatocellular carcinoma (HCC) is the sixth most common form of cancer and the fourth leading cause of cancer-related deaths worldwide with a 5-year survival rate of 15% [1], [2]. Due to the diverse factors contributing to its pathophysiology, such as hepatitis virus B/C infection, underlying liver disease, gender, and ethnicity/race, HCC is a highly heterogeneous tumor type with limited targeted therapeutic options [3], [4], [5]. Since the molecular pathogenesis of HCC depends on the etiologies associated with underlying liver disease, there is no one “driver” mutation. Indeed, there are few dominant driver mutations, including TERT, TP53, and CTNNB1, that are commonly observed in most HCCs [6], [7]. Global transcriptome analyses have revealed that HCC can be categorized into two molecular subclasses, proliferation and non-proliferation, which is associated with specific genomic alterations and clinical outcomes [4]. Although these alterations are signatures of disease, what causes these large changes is not well known.
RNA binding proteins (RBPs) are highly conserved and abundant proteins that are involved in all aspects of RNA regulation, including transcription [8] translation [9], splicing [10], [11], polyadenylation [12], stability [13], and localization [14]. RBPs can form dynamic protein complexes called ribonucleoprotein complexes (RNPs) through direct interaction with other proteins or as a scaffold with coding or non-coding RNAs. There are ∼ 1,500 experimentally validated RBPs in humans, which represents approximately 7% of coding genes [15]. RBPs are essential in many RNA processes and function as key regulators of cellular homeostasis and their dysregulation has been linked to several human diseases, including muscular atrophies, neurological disorders, and cancer [8], [16] (Fig. 1). These alterations include gene mutations, gene copy number alterations, aberrant subcellular localization, transcription or translation [17], [18]. Specifically, these alterations have been shown to occur during different stages of HCC progression, including steatosis, fibrosis, cirrhosis, and early HCC [19]. Considering the important roles that RBPs play in cellular maintenance and HCC progression, a deeper understanding of their molecular functions will aid in novel drug design and biomarker discovery.
Section snippets
Molecular mechanisms of RBPs in HCC
In eukaryotic cells, gene expression is regulated at both the transcriptional and post-transcriptional level. Many genes are involved in these processes, including RBPs which act as regulators of alternative splicing, mRNA export, mRNA stability, and translation [20]. RBPs also participate in the formation of ribonucleoprotein complexes such as the ribosome and spliceosome to maintain the accuracy of translation and splicing [21]. During transcription, RBPs can interact with nascent RNA to
RBPs and hepatitis virus
Amid the multiple risk factors that can cause HCC, the most common is chronic hepatitis HBV infection, which accounts for more than 50% of all cases [143]. Approximately 60% of HCC cases in Asia and Africa are HBV positive [4], [144], [145]. HBc protein is the core protein of hepatitis B virus, which plays an important role in RNA packaging, reverse transcription, and viral assembly. RBPs in the host cell can regulate the biology of HBV by interacting with HBc or target the virus RNA to
Potential biomarkers of liver cancer
Previous research has shown that RBPs can play a distinct role in the biochemical development and progression of HCC [25], [26]. Similar to biomarkers utilized in other cancers, this distinction can, in some cases, be correlated to prognosis and outcomes [25]. Therefore, deregulation of RBPs can be linked to unique subtypes of HCC, serving as potential biomarkers. The first broad class of proteins that may be useful in this capacity would be RNA-binding motif (RBM) proteins. RBMs, such as RBM3,
Conclusion and future perspectives
RBPs have been widely studied due to their involvement in multiple cellular processes. One of the main functions of RBPs is to form RNP units, or protein–protein complexes, to interact with each other or other RNA species. Such species include mRNAs, miRNAs, or lncRNAs to form a complex regulatory network. In these networks, RBPs are the key component. Considering their important role in the cell biology, studies have focused on the dysregulation of RBPs in cancer [203]. Early studies have
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by grants from the American Liver Foundation (A20-0085), American Gastroenterological Association Research Foundation's AGA-Elsevier Pilot Research Award (AGA2020-21-04), and the startup funds from Thomas Jefferson University and Sidney Kimmel Cancer Center (Philadelphia, PA; to H. Dang). We would also like to thank Rajkumar Baldeosingh for his assistance in editing the manuscript.
References (209)
- et al.
The human RBPome: from genes and proteins to human disease
Journal of proteomics
(2015) - et al.
Comprehensive Genomic Characterization of RNA-Binding Proteins across Human Cancers
Cell Rep
(2018) - et al.
RNA-binding proteins and post-transcriptional gene regulation
FEBS Lett
(2008) - et al.
The c-Myc target gene network
Semin Cancer Biol
(2006) - et al.
The Functional Impact of Alternative Splicing in Cancer
Cell Rep
(2017) - et al.
Determination of the RNA binding specificity of the heterogeneous nuclear ribonucleoprotein (hnRNP) H/H'/F/2H9 family
J Biol Chem
(2001) - et al.
HNRNPH1 is required for rhabdomyosarcoma cell growth and survival
Oncogenesis
(2018) - et al.
Hepatic Knockdown of Splicing Regulator Slu7 Ameliorates Inflammation and Attenuates Liver Injury in Ethanol-Fed Mice
Am J Pathol
(2018) - et al.
Alternative polyadenylation of mRNA and its role in cancer
Genes Dis
(2021) - et al.
Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells
Cell
(2009)
A mechanism for the regulation of pre-mRNA 3' processing by human cleavage factor Im
Mol Cell
Purification and characterization of human cleavage factor Im involved in the 3' end processing of messenger RNA precursors
J Biol Chem
Human pre-mRNA cleavage factor Im is related to spliceosomal SR proteins and can be reconstituted in vitro from recombinant subunits
Mol Cell
Global Positioning System: Understanding Long Noncoding RNAs through Subcellular Localization
Mol Cell
Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR
Mol Cell
Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability
Mol Cell
The mitochondrial RNA-binding protein GRSF1 localizes to RNA granules and is required for posttranscriptional mitochondrial gene expression
Cell Metab
Comparison of hepatocellular carcinoma in Eastern versus Western populations
Cancer
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
CA Cancer J Clin
Tumor Heterogeneity in Hepatocellular Carcinoma: Facing the Challenges, Liver
Cancer
Hepatocellular carcinoma
Nat Rev Dis Primers
A global view of hepatocellular carcinoma: trends, risk, prevention and management
Nat Rev Gastroenterol Hepatol
Dissecting the expression landscape of RNA-binding proteins in human cancers
Genome biology
Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged
Genes Dev
SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells
RNA Biol
CFIm25 links alternative polyadenylation to glioblastoma tumour suppression
Nature
HuR contributes to cyclin E1 deregulation in MCF-7 breast cancer cells
Cancer Res
Spatial regulation of beta-actin translation by Src-dependent phosphorylation of ZBP1
Nature
TERT promoter mutations in familial and sporadic melanoma
Science
Genome-wide analysis of noncoding regulatory mutations in cancer
Nature genetics
RNA Binding Proteins Control Transdifferentiation of Hepatic Stellate Cells into Myofibroblasts
Cell Physiol Biochem
RNA-binding proteins and their role in kidney disease
Nat Rev Nephrol
RNA-binding proteins in human genetic disease
Nature reviews. Genetics
Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma
Cancer Res
A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients
Cancer Res
NELFE-Dependent MYC Signature Identifies a Unique Cancer Subtype in Hepatocellular Carcinoma
Sci Rep
Human transcription elongation factor NELF: identification of novel subunits and reconstitution of the functionally active complex
Mol Cell Biol
Overexpression of the RD RNA binding protein in hepatitis C virus-related hepatocellular carcinoma
Oncol Rep
Alternative splicing as a regulator of development and tissue identity
Nat Rev Mol Cell Biol
Roles and mechanisms of alternative splicing in cancer - implications for care
Nat Rev Clin Oncol
Alternative splicing: the pledge, the turn, and the prestige : The key role of alternative splicing in human biological systems
Hum Genet
Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches
Nat Rev Mol Cell Biol
Mechanisms and Regulation of Alternative Pre-mRNA Splicing
Annu Rev Biochem
Identification of recurrent regulated alternative splicing events across human solid tumors
Nucleic Acids Res
Splicing alterations contributing to cancer hallmarks in the liver: central role of dedifferentiation and genome instability
Transl Gastroenterol Hepatol
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These authors contributed equally.