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. 2020 Nov 6;12(21):21638-21659.
doi: 10.18632/aging.103959. Epub 2020 Nov 6.

Analysis of METTL3 and METTL14 in hepatocellular carcinoma

Xiangxiang Liu  1 , Jian Qin  2 , Tianyi Gao  2 , Chenmeng Li  1 , Xiaoxiang Chen  2 , Kaixuan Zeng  1 , Mu Xu  2 , Bangshun He  2 , Bei Pan  2 , Xueni Xu  1 , Yuqin Pan  2 , Huiling Sun  2 , Tao Xu  2 , Shukui Wang  1   3
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Analysis of METTL3 and METTL14 in hepatocellular carcinoma

Xiangxiang Liu et al. Aging (Albany NY). .

Abstract

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.

Keywords: METTL14; METTL3; N6-methyladenosine; bioinformatics analysis; hepatocellular carcinoma.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
The opposite expression and prognostic value of METTL3 and METTL14 in HCC. (A, B) The expression of METTL3 in HCC tissues and NTs based on the TCGA database and GSE14520 analysis. (C, D) The expression of METTL14 in HCC tissues and NTs based on the TCGA database and GSE14520 analysis. (E) IHC analysis of METTL3 and METTL14 in HCC tissues and adjacent NTs. (F) The associations between METTL3 expression and OS, RFS, PFS, and DSS of HCC patients. (G) The associations between METTL14 expression and OS, RFS, PFS, and DSS of HCC patients. * p<0.05, *** p<0.001.
Figure 2
Figure 2
The DEGs regulated by METTL3 and METTL14 knockdown participate in different signaling pathways and biological processes. (A, B) The DEGs regulated by METTL3 and METTL14 knockdown. (C) Integrated analysis of M3DEGs and M14DEGs. (D, E) KEGG pathway analysis of M3DEGs and M14DEGs. (F) The number of biological processes regulated by M3DEGs and M14DEGs. (G) The common biological processes regulated by M3DEGs and M14DEGs.
Figure 3
Figure 3
The signaling pathways and biological processes of m6A modified M3DEGs. (A) The chromosome location of transcripts having m6A peaks in HepG2 cell. (B) The number of genes with various m6A peaks. (C) The distribution of m6A peaks in transcripts. (D) Integrated analysis of M3DEGs and mRNAs with m6A peaks. (E) KEGG pathway analysis of m6A modified M3DEGs. (F, G) KEGG pathway and GO enrichment analysis of functional molecular clusters among the PPI network of m6A modified M3DEGs. (H) The top 30 hub genes among m6A modified M3DEGs.
Figure 4
Figure 4
The signaling pathways and biological processes of m6A modified M14DEGs. (A) Integrated analysis of M14DEGs and mRNAs with m6A peaks. (B) KEGG pathway analysis of m6A modified M14DEGs. (C, D) KEGG pathway and GO enrichment analysis of functional molecular clusters among the PPI network of m6A modified M14DEGs. (E) The top 30 hub genes among m6A modified M14DEGs.
Figure 5
Figure 5
The TEGs regulated by METTL3 and METTL14 knockdown participate in distinct signaling pathways and biological processes. (A, B) The TEGs regulated by METTL3 and METTL14 knockdown. (C) Integrated analysis of M3TEGs and M14TEGs. (D, E) KEGG pathway analysis of M3TEGs and M14TEGs. (F) The number of biological processes regulated by M3TEGs and M14TEGs. (G) The common biological processes regulated by M3TEGs and M14TEGs.
Figure 6
Figure 6
The signaling pathways and biological processes of m6A modified M3TEGs. (A) Integrated analysis of M3TEGs and mRNAs with m6A peaks. (B) KEGG pathway analysis of m6A modified M3TEGs. (C, D) KEGG pathway and GO enrichment analysis of functional molecular clusters among PPI network of m6A modified M3TEGs. (E) The top 30 hub genes among m6A modified M3TEGs.
Figure 7
Figure 7
The signaling pathways and biological processes of m6A modified M14TEGs. (A) Integrated analysis of M14TEGs and mRNAs with m6A peaks. (B) KEGG pathway analysis of m6A modified M14TEGs. (C, D) KEGG pathway and GO enrichment analysis of functional molecular clusters among the PPI network of m6A modified M14TEGs. (E) The top 30 hub genes among m6A modified M14TEGs.
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