AHNAK loss in mice promotes type II pneumocyte hyperplasia and lung tumor development

Abstract

AHNAK is known to be a tumor suppressor in breast cancer due to its ability to activate the TGF beta signaling pathway. However, the role of AHNAK in lung tumor development and progression remains unknown. Here, the Ahnak gene was disrupted to determine its effect on lung tumorigenesis and the mechanism by which it triggers lung tumor development was investigated. First, AHNAK protein expression was determined to be decreased in human lung adenocarcinomas compared with matched nonneoplastic lung tissues. Then, Ahnak(-/-) mice were used to investigate the role of AHNAK in pulmonary tumorigenesis. Ahnak(-/-) mice showed increased lung volume and thicker alveolar walls with type II pneumocyte hyperplasia. Most importantly, approximately 20% of aged Ahnak(-/-) mice developed lung tumors, and Ahnak(-/-) mice were more susceptible to urethane-induced pulmonary carcinogenesis than wild-type mice. Mechanistically, Ahnak deficiency promotes the cell growth of lung epithelial cells by suppressing the TGF beta signaling pathway. In addition, increased numbers of M2-like alveolar macrophages (AM) were observed in Ahnak(-/-) lungs, and the depletion of AMs in Ahnak(-/-) lungs alleviated lung hyperplastic lesions, suggesting that M2-like AMs promoted the progression of lung hyperplastic lesions in Ahnak-null mice. Collectively, AHNAK suppresses type II pneumocyte proliferation and inhibits tumor-promoting M2 alternative activation of macrophages in mouse lung tissue. These results suggest that AHNAK functions as a novel tumor suppressor in lung cancer. (C) 2018 AACR.