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

Jun Won Park, Il Yong Kim, Ji Won Choi, Hee Jung Lim, Jae Hoon Shin, Yo Na Kim, Seo Hyun Lee, Yeri Son, Mira Sohn, Jong Kyu Woo, Joseph H. Jeong, Cheolju Lee, Yun Soo Bae, Je Kyung Seong

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

AHNAK is known to be a tumor suppressor in breast cancer due to its ability to activate the TGFb 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 TGFb 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. Implications: The tumor suppressor function of AHNAK, in murine lungs, occurs by suppressing alveolar epithelial cell proliferation and modulating lung microenvironment.

Original languageEnglish
Pages (from-to)1287-1298
Number of pages12
JournalMolecular Cancer Research
Volume16
Issue number8
DOIs
StatePublished - Aug 2018

Fingerprint

Dive into the research topics of 'AHNAK loss in mice promotes type II pneumocyte hyperplasia and lung tumor development'. Together they form a unique fingerprint.

Cite this