Fig. 4: Mechanisms of epigenetic regulation by direct interference by microRNAs (miRNA) and epitranscriptomic RNA modifications.

In HCC, direct miRNA interference contributes to HCC in two mechanisms. Firstly, oncogenic miRNAs degrade tumor-suppressive mRNAs and inhibit ribosomal translation. Secondly, tumor-suppressive miRNAs, which normally suppress the expression of proto-oncogenes in normal cells, are downregulated in HCC. Additionally, some epitranscriptomic changes include hypermethylation of tumor suppressor mRNA, which hinders ribosomal translation. Interestingly, hypomethylation of tumor suppressor mRNA can result in a loss in function through destabilization and degradation of mRNA. These result in increased translation of oncogenic mRNAs. Altogether, these might lead to HCC development through hepatic inflammation and metabolic dysregulation, evasion of cell death, unregulated proliferation, invasion, metastasis, and tumor microenvironment remodeling that favors hepatocarcinogenesis.