CircMETTL15 induces TMTC3 production by absorbing miR‐944 to promote hepatocellular carcinoma cell malignancy

Abstract Previous data have suggested the involvement of circular RNA (circRNA) in hepatocellular carcinoma (HCC) progression. Up to now, the effect of circMETTL15 on HCC development remains unknown. This study aims to analyze the function of circMETTL15 in HCC development and the underlying mechanism. RNA expression of circMETTL15, miR‐944, and transmembrane O‐mannosyltransferase targeting cadherins 3 (TMTC3) were detected by quantitative real‐time polymerase chain reaction (qRT‐PCR). Protein expression was evaluated by Western blot analysis assay or immunohistochemistry assay. Cell proliferation was investigated by cell counting kit‐8 assay, 5‐Ethynyl‐29‐deoxyuridine (EdU) assay, and cell colony formation assay. Cell migration and invasion were assessed by wound‐healing assay and transwell assay, respectively. Angiogenic capacity was analyzed by tube formation assay. Dual‐luciferase reporter assay and RNA immunoprecipitation assay were conducted to identify the interplay between miR‐944 and circMETTL15 or TMTC3. Xenograft mouse model assay was conducted to reveal the effect of circMETTL15 on tumor formation in vivo. CircMETTL15 and TMTC3 expression were significantly upregulated, while miR‐944 expression was downregulated in HCC tissues and cells. CircMETTL15 knockdown led to decreased cell proliferation, migration, invasion, and tube formation. Besides, the inhibitors of miR‐944, a target miRNA of circMETTL15, partially restored circMETTL15 silencing‐mediated effects on the proliferation, migration, invasion, and tube formation of HCC cells. MiR‐944 overexpression also inhibited HCC cell malignancy by targeting TMTC3. Furthermore, circMETTL15 absence inhibited tumor formation by regulating miR‐944 and TMTC3 in vivo. In conclusion, circMETTL15 induced HCC development through the miR‐944/TMTC3 pathway, raising the potential of circMETTL15 as a target for HCC therapy.