The functional roles, cross-talk and clinical implications of m6A modification and circRNA in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. HCC has high rates of death and recurrence, as well as very low survival rates. N6-methyladenosine (m6A) is the most abundant modification in eukaryotic RNAs, and circRNAs are a class of circular noncoding RNAs that are generated by back-splicing and they modulate multiple functions in a variety of cellular processes. Although the carcinogenesis of HCC is complex, emerging evidence has indicated that m6A modification and circRNA play vital roles in HCC development and progression. However, the underlying mechanisms governing HCC, their cross-talk, and clinical implications have not been fully elucidated. Therefore, in this paper, we elucidated the biological functions and molecular mechanisms of m6A modification in the carcinogenesis of HCC by illustrating three different regulatory factors ("writer", "eraser", and "reader") of the m6A modification process. Additionally, we dissected the functional roles of circRNAs in various malignant behaviors of HCC, thereby contributing to HCC initiation, progression and relapse. Furthermore, we demonstrated the cross-talk and interplay between m6A modification and circRNA by revealing the effects of the collaboration of circRNA and m6A modification on HCC progression. Finally, we proposed the clinical potential and implications of m6A modifiers and circRNAs as diagnostic biomarkers and therapeutic targets for HCC diagnosis, treatment and prognosis evaluation.