WTAP contributes to the malignancy and stemness of hepatocellular carcinoma through upregulating N6-methyladenosine modification of ITGB4.

[BACKGROUND] m6A modification is important in cancer progression. In the research, we explored the functions and mechanisms of WTAP (the key component of m6A) in HCC.

[METHODS] Expression of WTAP and ITGB4 was examined by qRT-PCR, western blot and IHC assays. Tumor cell proliferation, apoptosis, metastasis and stemness were investigated via colony formation, flow cytometry, transwell and sphere formation assays. The interaction between WTAP and ITGB4 was estimated by RIP, meRIP and dual-luciferase reporter experiments.

[RESULTS] ITGB4 was upregulated in HCC. Knockdown of ITGB4 repressed HCC cell growth, motility and stemness, accelerated HCC cell apoptosis in vitro, and blocked tumorigenesis in vivo. Through SRAMP website and a series experiments, WTAP catalysed m6A modification on ITGB4 mRNA, recognized by the reader YTHDF1, leading to increased mRNA stability. WTAP overexpression aggravated the malignant behaviors and stemness of HCC cells, with ITGB4 deficiency abrogated the effects. In addition, we demonstrated that WTAP could activate FAK/PI3K/AKT signaling pathway via regulating ITGB4 expression.

[CONCLUSION] WTAP mediated the m6A methylation modification of ITGB4 to promote HCC progression and tumor stemness, providing a new idea for HCC therapy.