Abstract
AHNAK is known to be a tumor suppressor in breast cancer due to its ability to activate the TGFβ 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 TGFβ 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. Mol Cancer Res; 16(8); 1287-98. ©2018 AACR.
Highlights
Lung cancer is the global leading cause of cancer-related mortality, and adenocarcinoma is the most common histologic type [1]
We performed IHC analysis using an antibody against Ahnak of a tissue microarray (TMA) slide containing 50 cases of human lung adenocarcinomas and matched normal lung tissues
Analysis of the Cancer Cell Line Encyclopedia database revealed that lung cancer cell lines have relatively lower AHNAK mRNA expression compared with other cancer cell lines
Summary
Lung cancer is the global leading cause of cancer-related mortality, and adenocarcinoma is the most common histologic type [1]. A number of genes commonly altered in human lung adenocarcinomas have been identified [2], and their roles in lung tumorigenesis have been evaluated using genetically engineered mouse (GEM) models [3]. GEM models expressing activating oncogenic mutants of the KRAS, EGFR, BRAF, and PIK3CA pathways developed lung tumors, and the combination of these mutants had synergistic effects on tumorigenesis and. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). J.W. Park and I.Y. Kim contributed to this article
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