Research Paper Volume 12, Issue 21 pp 21638—21659

Analysis of METTL3 and METTL14 in hepatocellular carcinoma

Xiangxiang Liu1, , Jian Qin2, , Tianyi Gao2, , Chenmeng Li1, , Xiaoxiang Chen2, , Kaixuan Zeng1, , Mu Xu2, , Bangshun He2, , Bei Pan2, , Xueni Xu1, , Yuqin Pan2, , Huiling Sun2, , Tao Xu2, , Shukui Wang1,3, ,

  • 1 School of Medicine, Southeast University, Nanjing 210096, Jiangsu, China
  • 2 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu, China
  • 3 Jiangsu Collaborative Innovation Center on Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211100, Jiangsu, China

Received: April 10, 2020       Accepted: August 1, 2020       Published: November 6, 2020
How to Cite

Copyright: © 2020 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


N6-methyladenosine (m6A) RNA methylation is the most prevalent modification of messenger RNAs (mRNAs) and catalyzed by a multicomponent methyltransferase complex (MTC), among which methyltransferase-like 3 (METTL3) and METTL14 are two core molecules. However, METTL3 and METTL14 play opposite regulatory roles in hepatocellular carcinoma (HCC). Based on The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, we conducted a multi-omics analysis of METTL3 and METTL14 in HCC, including RNA-sequencing, m6ARIP-sequencing, and ribosome-sequencing profiles. We found that the expression and prognostic value of METTL3 and METTL14 are opposite in HCC. Besides, after METTL3 and METTL14 knockdown, most of the dysregulated mRNAs, signaling pathways and biological processes are distinct in HCC, which partly explains the contrary regulatory role of METTL3 and METTL14. Intriguingly, these mRNAs whose stability or translation efficiency are influenced by METTL3 or METTL14 in an m6A dependent manner, jointly regulate multiple signaling pathways and biological processes, which supports the cooperative role of METTL3 and METTL14 in catalyzing m6A modification. In conclusion, our study further clarified the contradictory role of METTL3 and METTL14 in HCC.


m6A: N6-methyladenosine; MTC: methyltransferase complex; METTL3: methyltransferase-like 3; METTL14: methyltransferase-like 14; HCC: hepatocellular carcinoma; TCGA: The Cancer Genome Atlas; GEO: Gene Expression Omnibus; DEGs: differentially expressed genes; mRNAs: messenger RNAs; 3’UTR: 3’untranslated region; WTAP: Wilms’ tumor 1-associating protein; KIAA1429: Vir Like M6A Methyltransferase Associated; RBM15: RNA Binding Motif Protein 15; ZC3H13: Zinc Finger CCCH-Type Containing 13; FTO: fat mass and obesity-associated protein; ALKBH5: alkylated DNA repair protein alkB homolog 5; YTHDC1: YTH Domain-Containing Protein 1; YTHDF1/2/3: YTH Domain Family, Member 1/2/3; IGF2BP1/2/3: Insulin Like Growth Factor 2 MRNA Binding Protein 1/2/3; CRC: colorectal cancer; SOX2: SRY-Box 2; siRNA: small interfere RNA; TE: translational efficiency; shRNA: short hairpin RNA; OS: overall survival; RFS: relapse-free survival; PFS: progression-free survival; DSS: disease-specific survival; EGA: European Genome-phenome Archive; HR: hazard ratio; TEG: genes with significantly changed TE; GO: Gene ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; STRING: Search Tool for the Retrieval of Interacting Genes; MCODE: Molecular Complex Detection; MCC: Maximal Clique Centrality; M14DEGs: DEGs regulated by METTL14; M3DEGs: DEGs regulated by METTL3; M3TEGs: TEGs regulated by METTL3; M14TEGs: TEGs regulated by METTL14; FHL2: four and a half LIM-only protein 2.