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Review
. 2024 Aug 20:15:1439485.
doi: 10.3389/fimmu.2024.1439485. eCollection 2024.

The role of RNA modifications in hepatocellular carcinoma: functional mechanism and potential applications

Jin-Xiu Liu  1 , Xiaoping Zhang  2 , Wen-Hua Xu  3 , Xiao-Dan Hao  1
Affiliations
Review

The role of RNA modifications in hepatocellular carcinoma: functional mechanism and potential applications

Jin-Xiu Liu et al. Front Immunol. .

Abstract

Hepatocellular carcinoma (HCC) is a highly aggressive cancer with a poor prognosis. The molecular mechanisms underlying its development remain unclear. Recent studies have highlighted the crucial role of RNA modifications in HCC progression, which indicates their potential as therapeutic targets and biomarkers for managing HCC. In this review, we discuss the functional role and molecular mechanisms of RNA modifications in HCC through a review and summary of relevant literature, to explore the potential therapeutic agents and biomarkers for diagnostic and prognostic of HCC. This review indicates that specific RNA modification pathways, such as N6-methyladenosine, 5-methylcytosine, N7-methylguanosine, and N1-methyladenosine, are erroneously regulated and are involved in the proliferation, autophagy, innate immunity, invasion, metastasis, immune cell infiltration, and drug resistance of HCC. These findings provide a new perspective for understanding the molecular mechanisms of HCC, as well as potential targets for the diagnosis and treatment of HCC by targeting specific RNA-modifying enzymes or recognition proteins. More than ten RNA-modifying regulators showed the potential for use for the diagnosis, prognosis and treatment decision utility biomarkers of HCC. Their application value for HCC biomarkers necessitates extensive multi-center sample validation in the future. A growing number of RNA modifier inhibitors are being developed, but the lack of preclinical experiments and clinical studies targeting RNA modification in HCC poses a significant obstacle, and further research is needed to evaluate their application value in HCC treatment. In conclusion, this review provides an in-depth understanding of the complex interplay between RNA modifications and HCC while emphasizing the promising potential of RNA modifications as therapeutic targets and biomarkers for managing HCC.

Keywords: 5-methylcytosine; N1-methyladenosine; N6-methyladenosine; N7-methylguanosine; biomarkers; hepatocellular carcinoma; therapeutic targets.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Diagram of RNA modification mechanisms. M1A is generally located in the 5’ end of mRNA and can be converted to m6A by Dimroth rearrangement (A). M6A, m5C, m1A modifications mediate mRNA processing, stability of RNA, post-translational protein modification, etc (B–D). M7G modification mainly affects tRNA and rRNA and mediates post-translational protein modification (E). M6A modification of mRNA reversely regulates chromatin (F). (Created with BioRender.com).
Figure 2
Figure 2
Diagram of the m6A modification mechanism. M6A “writers”, including METTL3/14 and WTAP, catalyze the m6A modification of adenosine on RNA. Removing the methylation of RNA needs the functions of m6A “erasers” that mainly consist of FTO and ALKBH5. M6A “readers” (such as YTHDF1/2/3 and others) recognize m6A modification sites and exert corresponding functions.
Figure 3
Figure 3
The molecular functions of m6A modification in HCC. M6A modifiers affect the proliferation, epithelial-mesenchymal transition (EMT), migration, autophagy, immune escape and drug resistance of HCC cells. (Created with BioRender.com).
Figure 4
Figure 4
RNA modification-related agents. Research has found that some agents act on RNA modified regulators, and can trigger a series of downstream effects. (Created with BioRender.com).
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by the Shandong Provincial Natural Science Foundation, China (ZR2020MC059 and RH2200000157).

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