Abstract
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.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide [1]
Non–small cell lung cancer (NSCLC), accounting for approximately 85% of all cases, is a major subgroup of lung cancer, which is often diagnosed at advanced stage and holds poor prognosis [2]
Detailed molecular analyses showed that those hyperplasic lesions exhibited strong YAP staining and high Ki67-positive rate (Fig. 1B), indicating that ectopic expression of YAP confers lung epithelial cells with high proliferating potential and YAP is sufficient to drive hyperplasia in the lung
Summary
Lung cancer is the leading cause of cancer-related death worldwide [1]. Non–small cell lung cancer (NSCLC), accounting for approximately 85% of all cases, is a major subgroup of lung cancer, which is often diagnosed at advanced stage and holds poor prognosis [2]. Adenocarcinoma (ADC) is one of the common histologic subtypes of NSCLC [3]. The pathogenesis of ADC is partially understood and new therapeutic options have substantially increased the survival of patients with ADC over the last decade, it still remains as largely incurable [4]. Further mechanistic insights into lung ADC carcinogenesis are urgently needed to pave the way for the development of effective therapeutic strategies. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/)
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