METTL3‐mediated maturation of miR‐589‐5p promotes the malignant development of liver cancer

Abstract

MiR‐589‐5p could promote liver cancer, but the specific mechanisms are largely unknown. This study examined the role and mechanisms of miR‐589‐5p in liver cancer. The expressions of miR‐589‐5p, METTL3 and m6A in liver cancers were determined by RT‐qPCR. The relationship between miR‐589‐5p and METTL3‐mediated m6A methylation was examined by m6A RNA immunoprecipitation. After transfection, the viability, migration, invasion and expressions of METTL3 and miR‐589‐5p in liver cancer cells were detected by CCK‐8, wound‐healing, transwell and RT‐qPCR. After the xenograft tumour was established in mice, the tumour volume was determined and the expressions of METTL3, miR‐589‐5p, MMP‐2, TIMP‐2, E‐cadherin, N‐cadherin and Vimentin in tumour tissue were detected by RT‐qPCR and Western blotting. In vitro study showed that miR‐589‐5p and METTL3 were highly expressed in liver cancer. METTL3 was positively correlated with miR‐589‐5p. METTL3 up‐regulated the expression of miR‐589‐5p and promoted the maturation of miR‐589‐5p. Overexpressed miR‐589‐5p and METTL3 promoted the viability, migration and invasion of liver cancer cells, while the effects of silencing miR‐589‐5p and METTL3 on the cells were the opposite. The effects of METTL3 overexpression and silencing were reversed by miR‐589‐5p inhibitor and mimic, respectively. In vivo study showed that METLL3 silencing inhibited the growth of xenograft tumour and the expressions of METTL3, MMP‐2, N‐cadherin and Vimentin, promoted the expressions of TIMP‐2 and E‐cadherin, while miR‐589‐5p mimic caused the opposite results and further reversed the effects of METLL3 silencing. In summary, this study found that METTL3‐mediated maturation of miR‐589‐5p promoted the malignant development of liver cancer.

RNA m6A methylation regulators in liver cancer

“…The expression of METTL3 increased gradually from grade 1 to grade 3, but the difference between grade 3 and grade 4 was not statistically significant. More importantly, METTL3 expression was not associated with HBV or HCV viral infection, suggesting that METTL3 upregulation may be a universal feature in the development of HCC with different etiologies [ 74 ] Overexpression of METTL3 can promote the proliferation and migration of HCC mainly because METTL3 can regulate the m6A modification of SOCS2 mRNA, it promotes the occurrence and development of liver cancer by reducing the stability of SOCS2 mRNA through m6A-YTHDF2-dependent pathways [ 75 , 76 ].…”

Interaction between N6-methyladenosine and autophagy in the regulation of bone and tissue degeneration

“…They have a variety of known functions, and at the same time, some of the non-coding RNAs have unknown functions. It was widely reported that m6A methylation is involved in mediating cell proliferation by the induction of miRNA maturation, and the translation and degradation of circRNA, and by altering the stability of lncRNAs ( Lin et al, 2020a ; Du et al, 2022 ; Liu and Jiang, 2022 ; Yan et al, 2022 ). METTL3-mediated m6A modification has been reported to promote the maturation of miR-146a-5p, which exacerbates the development of bladder cancer ( Yan et al, 2022 ).…”

“…METTL3-mediated m6A modification has been reported to promote the maturation of miR-146a-5p, which exacerbates the development of bladder cancer ( Yan et al, 2022 ). Furthermore, METTL3 was previously demonstrated to enhance the binding ability of pri-miRNA-589–5p with DGCR8, promoting the malignant progression of hepatoma ( Liu and Jiang, 2022 ). Similarly, a recent study indicated that deoxycholic acid could suppress tumor development by decreasing the maturation of miR-92b-3p in a m6A-dependent manner ( Lin et al, 2020a ).…”

Clinical significance of RNA methylation in hepatocellular carcinoma

“…Upregulation of miR6079 leads to increased histone H3 methylation (H3K9me3) and subsequent activation of the proto-oncogene Pim1, ultimately enhancing cell proliferation in HCC Hep3B cells [ 81 ]. In addition, METTL3 increases the expression of miR-589-5p and mediates the aggressive viability, migration, and invasion of Hep3B and SK-Hep1 cells [ 82 ]. As a noncanonical m6A methyltransferase, high expression of KIAA1429 in HCC SK-Hep1 and HCCLM3 cells mediates m6A methylation of the mRNA of GATA binding protein 3 (GATA3) precursor; this decreases the levels of GATA3 and promotes tumor growth and metastasis [ 83 ].…”

“…For m6A modification, METTL3 overexpression is associated with poor prognosis in HCC, along with larger tumor size, worse Edmondson–Steiner grade, and advanced tumor stage [ 82 , 89 ]. In addition, the diagnostic value of KIAA1429 level has been confirmed through receiver operating characteristic curve analysis in multiple HCC cohorts [ 83 ].…”