The CRTC1-NEDD9 signaling axis mediates lung cancer progression caused by LKB1 loss.
The CRTC1-NEDD9 signaling axis mediates lung cancer progression caused by LKB1 loss.
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DOI：
10.1158/0008-5472.can-12-1909
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发表时间：
2012-12-15
期刊：
影响因子：
11.2
通讯作者：
Ji H
中科院分区：
文献类型：
--
作者：
Feng Y;Wang Y;Wang Z;Fang Z;Li F;Gao Y;Liu H;Xiao T;Li F;Zhou Y;Zhai Q;Liu X;Sun Y;Bardeesy N;Wong KK;Chen H;Xiong ZQ;Ji H
肿瘤抑制基因LKB 1的体细胞突变在肺癌中频繁发生，它导致肿瘤进展和转移，但其潜在机制仍然主要未知。在这里，我们表明，癌基因NEDD9是一个重要的下游介导的肺癌进展引起LKB 1的损失。在新生小鼠模型中，RNAi介导的Nedd9沉默抑制了肺肿瘤进展，而异位NEDD9表达加速了这一过程。从机制上讲，LKB 1通过促进CRTC1从细胞核的胞质移位来负调节NEDD 9的转录。值得注意的是，NEDD9或CRTC1的异位表达部分逆转了LKB 1对肺癌细胞转移的抑制功能。在临床标本中，NEDD9的高表达与恶性进展和转移相关。总的来说，我们的研究结果破译了LKB 1缺陷促进肺癌进展和转移的机制，并为这些过程的治疗攻击提供了机制依据。
Somatic mutation of the tumor suppressor gene LKB1 occurs frequently in lung cancer where it causes tumor progression and metastasis, but the underlying mechanisms remain mainly unknown. Here, we show that the oncogene NEDD9 is an important downstream mediator of lung cancer progression evoked by LKB1 loss. In de novo mouse models, RNAi-mediated silencing of Nedd9 inhibited lung tumor progression, whereas ectopic NEDD9 expression accelerated this process. Mechanistically, LKB1 negatively regulated NEDD9 transcription by promoting cytosolic translocation of CRTC1 from the nucleus. Notably, ectopic expression of either NEDD9 or CRTC1 partially reversed the inhibitory function of LKB1 on metastasis of lung cancer cells. In clinical specimens, elevated expression of NEDD9 was associated with malignant progression and metastasis. Collectively, our results decipher the mechanism through which LKB1 deficiency promotes lung cancer progression and metastasis, and provide a mechanistic rationale for therapeutic attack of these processes.