Abstract
N6-methyladenosine (m6A) is the most abundant mRNA modification in mammals and has been implicated in various biological processes. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. In this study, we investigated the alterations of 19 main m6A regulatory genes in HCC and their association with clinicopathological features, including survival. The mutation, copy number variation (CNV) and clinical data of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) database. We found that the m6A regulators had high frequent alterations in HCC. The alterations of m6A regulators were significantly associated with clinicopathological features as well as TP53 alteration. Patients with any mutation of the m6A regulatory genes had worse overall survival (OS) and disease free survival (DFS). Deletion of METTL16 or ALKBH5 predicted poor OS and DFS of HCC patients. Moreover, deletion of METTL16 was an independent risk factor for DFS. Low METT16 expression was association with activation of multiple metabolic pathways in HCC. Finally, by RT-PCR, we confirmed that METTL16 was downregulated in HCC, and that lower METTL16 expression was associated with poor OS. In conclusion, we reported a significant association between alterations of m6A regulators and clinicopathological features, and highlighted the importance of METTL16 among the 19 m6A regulators in HCC pathogenesis. These findings will provide new insights into the role of m6A modification in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, resulting in over 500,000 deaths per year (Torre et al, 2015)
We evaluated the relationship between the alterations of m6A regulatory genes and the clinicopathological features of hepatocellular carcinoma (HCC) patients
We investigated the association of METTL16 mRNA expression and patient survival in The Cancer Genome Atlas (TCGA) HCC dataset
Summary
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, resulting in over 500,000 deaths per year (Torre et al, 2015). It is reported that the m6A modification level of total RNA is decreased in HCC, and that METTL14 is the main factor involved in the aberrant m6A modification (Ma et al, 2017). Another study demonstrated that the high expression of METTL3 in HCC led to increased tumor growth and m6A modification level, mediating degradation of the tumor suppressor SOCS2 through an m6A reader protein YTHDF2dependent pathway (Chen et al, 2018). Knockdown of METTL14 significantly suppressed HCC cell proliferation and migration (Chen et al, 2018) These findings underscore the complexity of m6A modification and its regulatory enzymes in HCC. The TCGA HCC cases were divided into two group (High and Low) according to the METTL16 expression level. Gene sets with normalized p-value < 0.05 and the false discovery rate (FDR) < 0.25 were considered to be significantly enriched
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