Abstract
<div>Abstract<p>Somatic mutation of the tumor suppressor gene <i>LKB1</i> 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 <i>LKB1</i> loss. In <i>de novo</i> mouse models, RNAi-mediated silencing of <i>Nedd9</i> inhibited lung tumor progression, whereas ectopic NEDD9 expression accelerated this process. Mechanistically, LKB1 negatively regulated <i>NEDD9</i> 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 <i>LKB1</i> deficiency promotes lung cancer progression and metastasis, and provide a mechanistic rationale for therapeutic attack of these processes. <i>Cancer Res; 72(24); 6502–11. ©2012 AACR</i>.</p></div>
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