VIM-AS1, which is regulated by CpG methylation, cooperates with IGF2BP1 to inhibit tumor aggressiveness via EPHA3 degradation in hepatocellular carcinoma

Abstract

Early tumor recurrence in hepatocellular carcinoma (HCC) remains a challenging area, as the mechanisms involved are not fully understood. While microvascular invasion is linked to early recurrence, established biomarkers for diagnosis and prognostication are lacking. In this study, our objective was to identify DNA methylation sites that can predict the outcomes of liver cancer patients and elucidate the molecular mechanisms driving HCC aggressiveness. Using DNA methylome data from HCC patient samples from the CGRC and TCGA databases, we pinpointed hypermethylated CpG sites in HCC. Our analysis revealed that cg02746869 acts as a crucial regulatory site for VIM-AS1 (vimentin antisense RNA1), a 1.8 kb long noncoding RNA. RNA sequencing of HCC cells with manipulated VIM-AS1 expression revealed EPHA3 as a pathogenic target of VIM-AS1, which performs an oncogenic function in HCC. Hypermethylation-induced suppression of VIM-AS1 significantly impacted HCC cell dynamics, particularly impairing motility and invasiveness. Mechanistically, reduced VIM-AS1 expression stabilized EPHA3 mRNA by enhancing the binding of IGF2BP1 to EPHA3 mRNA, leading to increased expression of EPHA3 mRNA and the promotion of HCC progression. In vivo experiments further confirmed that the VIM-AS1‒EPHA3 axis controlled tumor growth and the tumor microenvironment in HCC. These findings suggest that the downregulation of VIM-AS1 due to hypermethylation at cg02746869 increased EPHA3 mRNA expression via a m6A-dependent mechanism to increase HCC aggressiveness. Despite advancements in treatment, cancer remains a life-threatening disease that can recur (come back) and metastasize. Researchers found a knowledge gap in understanding how DNA methylation affects cancer progression. Researchers conducted an experiment to identify DNA methylation markers related to liver cancer prognosis. They used human liver cancer cell lines and analyzed DNA methylation and gene expression. The researchers discovered that hypermethylation of a specific DNA region in the VIM-AS1 gene is linked to poor prognosis in liver cancer. They concluded that DNA methylation affects gene expression and cancer cell behavior. This finding could lead to new diagnostic and treatment strategies for liver cancer. Future research may explore how to target these epigenetic changes for better cancer therapies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.