Abstract
Purpose: N6-methyladenosine (m6A) RNA methylation has been implicated in various malignancies. This study aimed to identify the m6A methylation regulator-based prognostic signature for hepatocellular carcinoma (HCC) as well as provide candidate targets for HCC treatment.Methods: The least absolute shrinkage and selection operator (LASSO) analyses were performed to identify a risk signature in The Cancer Genome Atlas (TCGA) datasets. The risk signature was further validated in International Cancer Genome Consortium (ICGC) and Pan-Cancer Analysis of Whole Genomes (PCAWG) datasets. Following transfection of short hairpin RNA (shRNA) targeting YTHDF1, the biological activities of HCC cells were evaluated by Cell Counting Kit-8 (CCK-8), wound-healing, Transwell, flow cytometry, and xenograft tumor assays, respectively. The potential mechanisms mediated by YTHDF1 were predicted by overrepresentation enrichment analysis (ORA)/gene set enrichment analysis (GSEA) and validated by Western blotting.Results: Overexpression of m6A RNA methylation regulators was correlated with malignant clinicopathological characteristics of HCC patients. The Cox regression and LASSO analyses identified a risk signature with five m6A methylation regulators (KIAA1429, ZC3H13, YTHDF1, YTHDF2, and METTL3). In accordance with HCC cases in TCGA, the prognostic value of risk signature was also determined in ICGC and PCAWG datasets. Following analyzing the expression and clinical implications in TCGA and Gene Expression Omnibus (GEO), YTHDF1 was chosen for further experimental validation. Knockdown of YTHDF1 significantly inhibited the proliferation, migration, and invasion of HCC cells, as well as enhanced the apoptosis in vitro. Moreover, silencing YTHDF1 repressed the growth of xenograft tumors in vivo. Mechanism investigation indicated that YTHDF1 might promote the aggressive phenotypes by facilitating epithelial–mesenchymal transition (EMT) and activating AKT/glycogen synthase kinase (GSK)-3β/β-catenin signaling.Conclusion: The current study identified a robust risk signature consisting of m6A RNA methylation regulators for HCC prognosis. In addition, YTHDF1 was a potential molecular target for HCC treatment.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks the fourth leading cause of deaths worldwide (Bray et al, 2018)
The YTHDF1 mRNA profiles were obtained from the International Cancer Genome Consortium (ICGC) and Pan-Cancer Analysis of Whole Genomes (PCAWG) datasets with Gene Expression Omnibus (GEO) datasets including GSE22058, GSE25097, GSE36376, GSE46444, GSE54236, GSE63698, GSE64041, and GSE76427
The interaction network among the 16 m6A RNA methylation regulators were predicted by STRING, in which KIAA1429, WTAP, YTHDF2, and METTL3 were considered as hub genes (Figure 1C)
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks the fourth leading cause of deaths worldwide (Bray et al, 2018). The major risk factors of HCC include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, non-alcoholic steatohepatitis (NASH), alcohol abuse, diabetes mellitus, and aflatoxin exposure (Makarova-Rusher et al, 2016). Exposure to these factors and genetic and epigenetic alterations progressively promote the initiation of HCC (Cancer Genome Atlas Research, 2017). Surgery resection, liver transplantation, and systematic therapy are conventional therapies for HCC. Despite progression in therapeutic strategies for HCC, the overall survival (OS) remains unsatisfactory due to a high rate of postsurgical recurrence and metastasis (Finn et al, 2018).
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