Targeting non-coding RNAs and N⁶-methyladenosine modification in hepatocellular carcinoma

Hepatocellular carcinoma (HCC), the most common form of primary liver cancers, accounts for a significant portion of cancer-related death globally. However, the molecular mechanisms driving the onset and progression of HCC are still not fully understood. Emerging evidence has indicated that non-protein-coding regions of genomes could give rise to transcripts, termed non-coding RNA (ncRNA), forming novel functional driving force for aberrant cellular activity. Over the past decades, overwhelming evidence has denoted involvement of a complex array of molecular function of ncRNAs at different stages of HCC tumorigenesis and progression. In this context, several pre-clinical studies have highlighted the potentials of ncRNAs as novel therapeutic modalities in the management of human HCC. Moreover, N⁶-methyladenosine (m⁶A) modification, the most prevalent form of internal mRNA modifications in mammalian cells, is essential for the governance of biological processes within cells. Dysregulation of m⁶A in ncRNAs has been implicated in human carcinogenesis, including HCC. In this review, we will discuss dysregulation of several hallmark ncRNAs (miRNAs, lncRNAs, and circRNAs) in HCC and address the latest advances for their involvement in the onset and progression of HCC. We also focus on dysregulation of m⁶A modification and various m⁶A regulators in the etiology of HCC. In the end, we discussed the contemporary preclinical and clinical application of ncRNA-based and m⁶A-targeted therapies in HCC.