Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer

Abstract

\n 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.