Multiple m6A RNA methylation modulators promote the malignant progression of hepatocellular carcinoma and affect its clinical prognosis

Abstract

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.

Transcriptome-Wide High-Throughput m6A Sequencing of Differential m6A Methylation Patterns in the Human Rheumatoid Arthritis Fibroblast-Like Synoviocytes Cell Line MH7A

“…In recent years, an increasing number of studies on m6A and diseases have been carried out. 31 , 32 However, the transcriptome-wide distributions of m6A modifications in MH7A cells and the specific function of m6A methylation differences in the pathogenesis of RA are not clear.…”

The emerging roles of m6A modification in liver carcinogenesis

“…YTHDF2 expression is closely associated with HCC malignance, and can be inhibited by miR-145 152 . YTHDF2, YTHDF1, METTL3, KIAA1429, and ZC3H13 could be a prognostic signature of malignant HCC patients 52 , 157 - 159 . The expression of two genes (hnRNPA2B1 and RBM15) are closely related to the TNM stage and metastasis risk and can act as a prognostic indicator for HBV-related HCC patients in the early TNM stage 160 .…”

“…Numerous studies have demonstrated an important role of epigenetic modifications including DNA and histone modification in regulating HCC progression 51 . There is increasing evidence that total m 6 A levels and abnormal expression of m 6 A regulators are altered and associated with HCC clinical prognosis 52 , 53 . Furthermore, the m 6 A modification regulators play an oncogenic or tumor suppressor role in HCC by influencing the expression of special genes 54 - 56 .…”

YTH Domain Proteins: A Family of m6A Readers in Cancer Progression

“…The analysis of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) databases and the immunohistochemical analysis have shown that YTHDF1 is upregulated, associated with poor overall survival (OS) and pathologic staging of liver cancer. YTHDF1 is an independent adverse prognostic factor involved in regulating the cell cycle and metabolism of liver cancer ( 23 , 70 , 71 ). Therefore, it is considered to be a cancer-promoting factor.…”