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Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer
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 show that OTU domain-containing protein 3 (OTUD3) i...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636640/ https://www.ncbi.nlm.nih.gov/pubmed/34853315 http://dx.doi.org/10.1038/s41467-021-27348-8 |
Sumario: | 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 show that OTU domain-containing protein 3 (OTUD3) is downregulated by nicotine and correlates with poor prognosis in heavy-smoking esophageal cancer patients. OTUD3 directly interacts with ZFP36 ring finger protein (ZFP36) and stabilizes it by inhibiting FBXW7-mediated K48-linked polyubiquitination. ZFP36 binds with the VEGF-C 3-‘UTR and recruits the RNA degrading complex to induce its rapid mRNA decay. Downregulation of OTUD3 and ZFP36 is 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, suggesting 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. |
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