TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer
TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer
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DOI：
10.1002/mc.22740
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发表时间：
2018-02-01
影响因子：
4.6
通讯作者：
Wang, Enhua
中科院分区：
文献类型：
--
作者：
Han, Yong;Tang, ZhongPing;Wang, Enhua
TNFAIP 8与几种人类恶性肿瘤的预后相关。然而，TNFAIP 8在肺癌中的分子机制仍不清楚。在我们的研究中，我们发现TNFAIP 8可以增强TEAD荧光素酶的活性，并抑制Hippo通路的活性。TNFAIP 8还增加肺癌细胞中的细胞周期蛋白D1、CDK 6，并降低p27。此外，TNFAIP 8增加总雅普蛋白，并促进雅普的核定位。更重要的是，雅普缺失阻断了TNFAIP 8对细胞周期相关蛋白和TEAD荧光素酶活性的作用，揭示了TNFAIP 8以YAP依赖的方式调节Hippo通路。进一步的实验表明TNFAIP 8缺失增强LATS 1磷酸化，TNFAIP 8过表达降低磷酸化LAST 1水平。LATS 1 siRNA处理逆转了TNFAIP 8质粒或siRNA对细胞周期蛋白的影响。此外，免疫荧光和免疫共沉淀实验证实TNFAIP 8与LATS 1在H460和H1299细胞中存在相互作用，提示TNFAIP 8通过与LATS 1相互作用调节Hippo信号转导。集落形成测定和transwell测定显示，雅普或LATS 1缺失逆转了TNFAIP 8对细胞增殖和侵袭的积极作用。TNFAIP 8过表达可增加MMP-7，TNFAIP 8缺失可在蛋白和mRNA水平降低MMP-7，而E-cadherin、N-cadherin和Vimentin无显著变化。总之，本研究提供了一个新的发现，TNFAIP 8通过与LATS 1相互作用调节Hippo通路，促进肺癌细胞的增殖和侵袭。TNFAIP 8可以作为预后不良的候选生物标志物和新疗法的靶点。
TNFAIP8 is associated with prognosis of several human malignancies. However, the molecular mechanism of TNFAIP8 in lung cancer remains unknown. In our study, we found TNFAIP8 could enhance TEAD luciferase activity and inhibits the activity of Hippo pathway. TNFAIP8 also increased cyclin D1, CDK6, and decreased p27 in lung cancer cells. In addition, TNFAIP8 increased total YAP protein and promoted nuclear localization of YAP. More importantly, YAP depletion blocked the role of TNFAIP8 on cell cycle-related proteins and TEAD luciferase activity, revealing that TNFAIP8 regulates Hippo pathway in a YAP-dependend manner. Further experiments identified that TNFAIP8 depletion enhanced LATS1 phosphorylation and TNFAIP8 overexpression decreased phosphorylated LAST1 level. LATS1 siRNA treatment reversed the effects of TNFAIP8 plasmid or siRNA on cell cycle proteins. Besides, immunofluorescence and co-immunoprecipitation demonstrated the interaction between TNFAIP8 and LATS1 in H460 and H1299 cells, suggesting that TNFAIP8 regulates Hippo signaling through its interaction with LATS1. Colony formation assays and transwell assays showed that YAP or LATS1 depletion reversed the positive effect of TNFAIP8 on cell proliferation and invasion. TNFAIP8 overexpression could increase MMP-7 and TNFAIP8 depletion could decrease MMP-7 at both protein and mRNA levels, without significant changes of E-cadherin, N-cadherin, and Vimentin. Collectively, the present study provides a novel finding that TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer. TNFAIP8 may serve as a candidate biomarker for poor prognosis and a target for new therapies.