Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer.
Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer.
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尼古丁介导的 OTUD3 下调抑制 VEGF-C mRNA 衰减，促进人食管癌淋巴转移。
DOI：
10.1038/s41467-021-27348-8
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发表时间：
2021-12-01
影响因子：
16.6
通讯作者：
Song L
中科院分区：
文献类型：
--
作者：
Wang M;Li Y;Xiao Y;Yang M;Chen J;Jian Y;Chen X;Shi D;Chen X;Ouyang Y;Kong L;Huang X;Bai J;Lin C;Song L
尼古丁成瘾和淋巴结转移的发生是食管癌预后不良的两个重要因素;然而，尼古丁在诱导食管癌淋巴结转移中的作用尚不清楚。在这里，我们表明，OTU结构域蛋白3（OTUD 3）被尼古丁下调，并与重度吸烟食管癌患者的预后不良相关。OTUD 3直接与ZFP 36环指蛋白（ZFP 36）相互作用，并通过抑制FBXW 7介导的K48连接的多聚泛素化来稳定它。ZFP 36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。食管癌中OTUD 3和ZFP 36的下调对尼古丁诱导的VEGF-C产生和淋巴转移至关重要本研究证实OTUD 3/ZFP 36/VEGF-C轴在尼古丁成瘾诱导的淋巴转移中起着至关重要的作用，表明OTUD 3可作为预后标志物，并且诱导VEGF-C mRNA衰减可能是针对人食管癌的潜在治疗策略。VEGF-C是如何通过调节促进食管癌淋巴转移的机制尚不清楚。在这里，作者表明尼古丁通过下调去泛素化酶OTUD 3和RNA结合蛋白ZFP 36来防止VEGF-C mRNA的mRNA衰减并促进淋巴转移。
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.
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