Journal
CANCER RESEARCH
Volume 75, Issue 21, Pages 4450-4457Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-3396
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Funding
- National Basic Research Program of China (973 Program) [2012CB910800, 2012CB945001]
- National Natural Science Foundation of China [81430066, 81402276, 81402371, 81401898, 81402498, 81101583, 81372509, 31370747, 81325015]
- Science and Technology Commission of Shanghai Municipality [12JC1409800, 15XD1504000]
- Cross and Cooperation in Science and Technology Innovation Team program, Shanghai Institutes for Biological Sciences [2013KIP303, 2013KIP102]
- China Postdoctoral Science Foundation [2011M500826]
- Second Military Medical University Youth Startup Funds [2013QN10]
- Youth Research Projects of Shanghai Municipal Bureau of Health [20134Y210]
- Sanofi-Aventis Shanghai Institutes for Biological Sciences (SA-SIBS) scholarship program
- K.C. Wong education foundation scholarship
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The serine/threonine kinase LKB1 is a well-characterized tumor suppressor that governs diverse cellular processes, including growth, polarity, and metabolism. Somatic-inactivating mutations in LKB1 are observed in about 15% to 30% of non-small cell lung cancers (NSCLC). LKB1 inactivation confers lung adenocarcinomas (ADC) with malignant features that remain refractory to therapeutic intervention. YAP activation has been linked to LKB1 deficiency, but the role of YAP in lung ADC formation and progression is uncertain. In this study, we showed that ectopic expression of YAP in type II alveolar epithelial cells led to hyperplasia in mouse lungs. YAP overexpression in the Kras(G12D) lung cancer mouse model accelerated lung ADC progression. Conversely, YAP deletion dramatically delayed the progression of lung ADC in LKB1-deficient Kras(G12D) mice. Mechanistic studies identified the antiapoptotic oncoprotein survivin as the downstream mediator of YAP responsible for promoting malignant progression of LKB1-deficient lung ADC. Collectively, our findings identify YAP as an important contributor to lung cancer progression, rationalizing YAP inhibition in the context of LKB1 deficiency as a therapeutic strategy to treat lung ADC. (C) 2015 AACR.
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