Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer
Abstract Nicotine addiction and the occurrence of lymph node spread are two major significant factors associated with esophageal cancer's poor prognosis; however, nicotine's role in inducing lymphatic metastasis of esophageal cancer remains unclear. Here we showed that OTU domain-containing protein 3 (OTUD3) was downregulated by nicotine and correlated with poor prognosis in heavy-smoking esophageal cancer patients. Nicotine-mediated OTUD3 downregulation promoted lymphatic metastasis by inducing substantial tumor-induced lymphangiogenesis. At the mechanistic level, OTUD3 directly interacted with ZFP36 ring finger protein (ZFP36) and stabilized it by inhibiting FBXW7-mediated K48-linked polyubiquitination. ZFP36 bound with the VEGF-C 3-'UTR and recruited the RNA degrading complex to induce its rapid mRNA decay. Thus, downregulation of OTUD3 and ZFP36 was essential for nicotine-induced VEGF-C production and lymphatic metastasis in esophageal cancer. This study establishes that the OTUD3/ZFP36/VEGF-C axis plays a vital role in nicotine addiction-induced lymphatic metastasis. It also suggests that OTUD3 may serve as a prognostic marker, and induction of the VEGF-C mRNA decay might be a potential therapeutic strategy against human esophageal cancer.