Hypoxia down-regulates METTL3 and WTAP activating Integrin/FAK signaling through m6A/IGF2BP3 dependent manners in TGFBI mRNA to promote pancreatic neuroendocrine neoplasms progression

Hypoxia along with N6-methyladenosine (m6A) plays crucial roles in human tumorigenesis by influencing nearly every aspect of RNA metabolism. Nevertheless, the physiological signals that regulate the equilibrium between methylation and demethylation under hypoxic conditions have yet to be elucidated. Furthermore, the role of m6A methylation-mediated adaptation to hypoxia and the resultant phenotypic shift in pancreatic neuroendocrine neoplasms (pNENs) has not been thoroughly investigated. In this study, we demonstrated a significant reduction in m6A levels in pNENs cells subjected to hypoxia, which was correlated with the advancement of pNENs. Mechanistically, hypoxia-induced downregulation of USP38 in pNENs cells led to diminished m6A levels by promoting ubiquitination-dependent degradation of METTL3 and WTAP. This reduction in m6A modification was mediated through IGF2BP3, resulting in decreased mRNA stability of TGFBI. Additionally, TGFBI was found to bind to Integrin β 1(ITGB1) and negatively regulated ITGB1, thus enhancing its expression in pNENs and promoting proliferation and metastasis via the activation of the Integrin/FAK pathway. These findings offer novel insights into the mechanisms by which tumor cells adapt to hypoxic environments and suggest potential novel therapeutic targets for pNENs.