Diagnostic, Therapeutic, and Prognostic Value of the m6A Writer Complex in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) has poor prognosis and is usually diagnosed only at an advanced stage. Identification of novel biomarkers is critical to early diagnosis and better prognosis for HCC patients. N6-methyladenosine (m6A) RNA methylation regulators play important roles in the development of many tumors. However, the m6A writer complex, a key executor of m6A methylation modification, has not been independently investigated, and its specific bioinformatics analysis has not yet been performed in HCC. In this study, we used multiple public databases to evaluate the diagnostic, therapeutic, and prognostic value of the m6A writers in HCC. The results showed that expression levels of METTL3, VIRMA and CBLL1 were significantly increased, while expression levels of METTL14 and ZC3H13 were significantly decreased in HCC, which was closely related to clinicopathological factors, such as tumor stage and prognosis. Bioinformatics further explored the possible underlying mechanisms by which the m6A writer complex are involved in activation of tumor-promoting pathways and/or inhibition of tumor-suppressing pathways, including apoptosis, cell cycle, DNA damage response and EMT. Furthermore, we showed that the m6A writer complex is correlated with immune cell infiltration and immunoregulator expression in HCC. In conclusion, the m6A writer complex may represent a promising biomarker and target that can guide targeted therapy or immunotherapy for HCC patients.

Relevance of RNA N6-Methyladenosine Regulators for Pulmonary Fibrosis: Implications for Chronic Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis

“…METTL3, the first identified gene in m6A modification, can interact with Per2 and Arntl to directly mediate the export of mRNA ( Bhattarai et al, 2021 ). METTL14, METTL16, WTAP, VIRMA, ZC3H13, CBLL1, RBM15, and RBM15B are also included in the complex of m6A “writers” ( Meyer and Jaffrey, 2017 ; Wen et al, 2018 ; Gu et al, 2022 ; Shen et al, 2022 ; Su et al, 2022 ). Accordingly, YT521-B homology (YTH) domain family is the main “readers” ( Jones et al, 2022 ) and “erasers” consisting of FTO and ALKBH5 ( Kaur et al, 2022 ).…”

The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer

“…First of all, the expression level of METTL14 was identified to be obviously decreased in HCC, which closely correlated with clinicopathological factors, including tumor stage and prognosis (Fig. 3) [125][126][127][128].…”

“…First of all, the expression level of METTL14 was identified to be obviously decreased in HCC, which closely correlated with clinicopathological factors, including tumor stage and prognosis (Fig. 3 ) [ 125 – 128 ]. Based on the analysis of data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), Liu et al showed the opposite expression level and prognostic value of METTL14 and METTL3 in HCC [ 127 ].…”

The role of RNA modification in hepatocellular carcinoma

“…The m6A, m7G, m5C, m1A, m3C, and ψ RNA modifications dynamically regulate the development of HCC, providing new strategies and possibilities for selecting possible therapeutic targets and investigating precisely directed intervention strategies for future HCC therapy (Tian et al, 2019;Bolatkan et al, 2022;Liu et al, 2022;Ren et al, 2022;Tong et al, 2022;Yu et al, 2022). As the most intensively studied RNA modification, m6A, and its regulators regulate the proliferation, migration, invasion, and EMT processes of HCC cells and are promising targets for HCC therapy (Zhou et al, 2019b;Liu et al, 2020a;Wang et al, 2020b;Zhang et al, 2020c;Qu et al, 2020;Wu et al, 2020;Zhu et al, 2020;Li et al, 2021e;Wei, 2021;Gu et al, 2022;Ren et al, 2022). Although m6A in mammalian RNA has been extensively studied, there is currently no evidence for DNA N6 -methyladenine in mammals (Douvlataniotis et al, 2020).…”