下调和上调
食管癌
尼古丁
淋巴系统
癌症
癌症研究
转移
信使核糖核酸
医学
癌细胞
内科学
化学
病理
生物化学
基因
作者
Meng Wang,Yue Li,Yunyun Xiao,Muwen Yang,Jinxin Chen,Yunting Jian,Xin Chen,Dongni Shi,Xiangfu Chen,Ying Ouyang,Lingzhi Kong,Xinjian Huang,Jiewen Bai,Chuyong Lin,Libing Song
标识
DOI:10.1038/s41467-021-27348-8
摘要
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.
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