Multiple m(6)A RNA methylation modulators promote the malignant progression of hepatocellular carcinoma and affect its clinical prognosis

BACKGROUND: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. N(6)-methyladenosine (m(6)A) RNA methylation is dynamically regulated by m(6)A RNA methylation modulators (“writer,” “eraser,” and “reader” proteins), which are associated with cancer occurrence and development. The purpose of this study was to explore the relationships between m(6)A RNA methylation modulators and HCC. METHODS: First, using data from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases, we compared the expression levels of 13 major m6A RNA methylation modulators between HCC and normal tissues. Second, we applied consensus clustering to the expression data on the m(6)A RNA methylation modulators to divide the HCC tissues into two subgroups (clusters 1 and 2), and we compared the clusters in terms of overall survival (OS), World Health Organization (WHO) stage, and pathological grade. Third, using least absolute shrinkage and selection operator (LASSO) regression, we constructed a risk signature involving the m(6)A RNA methylation modulators that affected OS in TCGA and ICGC analyses. RESULTS: We found that the expression levels of 12 major m6A RNA methylation modulators were significantly different between HCC and normal tissues. After dividing the HCC tissues into clusters 1 and 2, we found that cluster 2 had poorer OS, higher WHO stage, and higher pathological grade. Four m(6)A RNA methylation modulators (YTHDF1, YTHDF2, METTL3, and KIAA1429) affecting OS in the TCGA and ICGC analyses were selected to construct a risk signature, which was significantly associated with WHO stage and was also an independent prognostic marker of OS. CONCLUSIONS: In summary, m(6)A RNA methylation modulators are key participants in the malignant progression of HCC and have potential value in prognostication and treatment decisions.