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Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer
Nature Communications ( IF 16.6 ) Pub Date : 2021-12-01 , DOI: 10.1038/s41467-021-27348-8
Meng Wang 1 , Yue Li 1 , Yunyun Xiao 1 , Muwen Yang 1 , Jinxin Chen 1 , Yunting Jian 1 , Xin Chen 2 , Dongni Shi 1 , Xiangfu Chen 1 , Ying Ouyang 1 , Lingzhi Kong 1 , Xinjian Huang 1 , Jiewen Bai 1 , Chuyong Lin 1, 3 , Libing Song 1, 2
Affiliation  

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.



中文翻译:

尼古丁介导的OTUD3下调抑制VEGF-C mRNA衰变促进人食管癌淋巴转移

尼古丁成瘾和淋巴结转移的发生是影响食管癌预后不良的两大重要因素;然而,尼古丁在诱导食管癌淋巴转移中的作用尚不清楚。在这里,我们显示含有 OTU 结构域的蛋白 3 (OTUD3) 被尼古丁下调,并与重度吸烟食管癌患者的不良预后相关。OTUD3 直接与 ZFP36 无名指蛋白 (ZFP36) 相互作用,并通过抑制 FBXW7 介导的 K48 连接的多聚泛素化来稳定它。ZFP36 与 VEGF-C 3-'UTR 结合并募集 RNA 降解复合物以诱导其快速 mRNA 衰变。OTUD3 和 ZFP36 的下调对于尼古丁诱导的 VEGF-C 产生和食管癌淋巴转移至关重要。

更新日期:2021-12-01
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