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

Abstract

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.

ENKUR expression induced by chemically synthesized cinobufotalin suppresses malignant activities of hepatocellular carcinoma by modulating β-catenin/c-Jun/MYH9/USP7/c-Myc axis

“…However, conventional HCC treatments, including surgical resection and transplantation, are only effective in patients diagnosed at early stages 3 . HCC is characterized with abnormal expression of a lot of genes 4 - 6 , which results in frequent occurrence and distant metastasis of tumor as well as poor prognosis of HCC patients 7 , 8 . So far, there is no particularly effective therapeutic options for advanced HCC patients 9 .…”

Identification of KRBA1 as a Potential Prognostic Biomarker Associated with Immune Infiltration and m6A Modification in Hepatocellular Carcinoma

“… 49 , 50 Based on the available reports, we found that different m6A-related factors are differentially expressed or functionally inconsistent in HCC, which may stem from the different biological functions triggered by the signalling pathways affected by the different downstream targets of m6A. 51 However, there is no research on the relationship between KRBA1 and m6A in tumors. Our results found a strong positive correlation between KRBA1 m6A modification and gene expression, especially for the five genes IGF2BP2, METTL3, YTHDF1, RBM15B, and HNRNPA2B1.…”

Mutual regulation between N6-methyladenosine (m6A) modification and circular RNAs in cancer: impacts on therapeutic resistance

“…As the main subtype of primary liver cancer, HCC comprises 75–85% of cases, which is one of the leading causes of cancer-related deaths worldwide [ 46 ]. In recent years, accumulating evidence has confirmed that circRNAs and m6A, especially their interplays, play key roles in many aspects of HCC [ 190 ]. For instance, METTL3 and YTHDC1 were uncovered to promote circHPS5 generation and cytoplasmic export in HCC, respectively.…”

“…With the accumulation of epigenetic studies, it has been gradually realized that aberrant epigenetic modifications of RNA, especially m6A modification may result in HCC occurrence, progression and even therapeutic resistance [ 190 ]. YTHDF1 belongs to the YTH domain family, which is responsible for the modulation of RNA translation.…”