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Authors Zhou Y, Yin Z, Hou BH, Yu M, Chen R, Jin H, Jian Z
Received 20 October 2018
Accepted for publication 1 April 2019
Published 1 May 2019 Volume 2019:11 Pages 3921—3931
DOI https://doi.org/10.2147/CMAR.S191565
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Andrew Yee
Peer reviewer comments 2
Editor who approved publication: Dr Chien-Feng Li
Background: N6-methyladenosine
(m6A) is the most prevalent modification of mammalian RNA. Emerging evidence
suggest that m6A has critical roles in multiple biological activities, but
little is known about its roles in cancer pathogenesis. Herein, we report the
expression profiles and prognostic relevance of twelve m6A-related genes in
hepatocellular carcinoma (HCC) by analyzing four independent datasets.
Materials and methods: RNA
levels of twelve m6A-related genes were detected in samples of 162 HCC patients
who underwent curative resection (the Guangdong General Hospital dataset). We
additionally analyzed the expression profiles of m6A-related genes in The Cancer
Genome Atlas liver HCC dataset and two Gene Expression Omnibus datasets
(GSE14520, GSE63898). Prognostic value of genes was evaluated by Kaplan–Meier
curves of overall survival (OS) with the log-rank test and multivariate Cox
regression analysis. Gene set enrichment analysis (GSEA) was conducted to
identify associated KEGG pathways.
Results: Five
genes (METTL3, YTHDF1, YTHDF2, YTHDF3, and EIF3) showed consistent upregulation
in all four datasets. Abnormal expressions of either METTL3 or YTHDF1 but not
the other ten genes were associated with OS. Protein expression of METTL3 and
YTHDF1 were confirmed in HCC tissues by immunohistochemical staining.
Multivariate Cox regression analysis confirmed the independent predictive value
of both METTL3 and YTHDF1 on OS. We further divided patients into three groups
based on the median expression values of METTL3 and YTHDF1. In all datasets,
the low METTL3/low YTHDF1 group showed a consistent better prognosis than other
groups. GSEA revealed that both METTL3 and YTHDF1 regulate HCC cell cycle, RNA
splicing, DNA replication, base excision repair, and RNA degradation.
Conclusion: Both
METTL3 and YTHDF1 were upregulated in HCC, and they were independent poor
prognostic factors. Combination of METTL3 and YTHDF1 can be regarded as the
biological marker that reflect malignant degree and evaluate prognosis in HCC.
Keywords: hepatocellular
carcinoma, N6-methyladenosine, m6A, prognosis