1. Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer
- Author
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Libing Song, Ying Ouyang, Dongni Shi, Meng Wang, Yunyun Xiao, Xin Chen, Muwen Yang, Yunting Jian, Jinxin Chen, Jiewen Bai, Lingzhi Kong, Xiangfu Chen, Xinjian Huang, Yue Li, and Chuyong Lin
- Subjects
Nicotine ,Esophageal Neoplasms ,Science ,RNA Stability ,Vascular Endothelial Growth Factor C ,Down-Regulation ,Mice, Nude ,General Physics and Astronomy ,MRNA Decay ,RNA decay ,Article ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,Mice ,Tristetraprolin ,Ubiquitin ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Animals ,Humans ,ZFP36 ,RNA, Messenger ,Lymph node ,Mice, Inbred BALB C ,Multidisciplinary ,biology ,business.industry ,RNA ,General Chemistry ,Esophageal cancer ,medicine.disease ,Gene Expression Regulation, Neoplastic ,HEK293 Cells ,medicine.anatomical_structure ,Lymphatic Metastasis ,biology.protein ,Cancer research ,Angiogenesis Inducing Agents ,Ubiquitin-Specific Proteases ,business ,Tumour angiogenesis ,medicine.drug - 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 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., The mechanism of how VEGF-C is regulated to promote lymphatic metastasis of oesophageal cancer is unclear. Here the authors show that nicotine prevents the mRNA decay of VEGF-C mRNA and promotes lymphatic metastasis by downregulating deubiquitinase OTUD3 and RNA binding protein ZFP36.
- Published
- 2021