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 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. The tumor suppressor function of AHNAK, in murine lungs, occurs by suppressing alveolar epithelial cell proliferation and modulating lung microenvironment. .

Paucimannosidic glycoepitopes inhibit tumorigenic processes in glioblastoma multiforme

“…It was demonstrated to act as a tumor suppressor in lung and breast cancer and in melanoma. In contrast, an upregulation and involvement in cancer cell migration and invasion in mesothelioma was reported [36–40]. Consistent with the latter hypothesis, AHNAK deficient keratinocytes exhibited reduced migration, invasion and metastatic properties [28].…”

<p>Long Intergenic Non-Protein Coding RNA 01089 Weakens Tumor Proliferation, Migration, and Invasion by Sponging miR-3187-3p in Non-Small Cell Lung Cancer</p>

“…37 A previous study found that AHNAK expression was significantly reduced in human lung adenocarcinomas compared with matched normal lung tissues, and reduced AHNAK expression enhanced Type II Pneumocyte Hyperplasia and expedited the lung tumor development. 38 AHNAK degradation could maintain the stemness of lung cancer stem-like cells. 39 Consistently, this study showed that AHNAK expression was significantly decreased in NSCLC tissues and cells.…”

Functions of Vertebrate Ferlins

“…In particular myoferlin is a part of a network promoting muscle growth, since (1) myoferlin knock-out in mice leads to smaller skeletal muscles due to reduced myofiber size [124]; (2) myoferlin enhances promitotic signaling by supporting recycling to the PM of the potent muscle growth stimulator IGF1R and preventing its degradation [125] and (3) myoferlin could possibly control the activity of the tumor suppressor and nuclear protein AHNAK and of ADAM12. Myoferlin and AHNAK interact and both can translocate to the nuclei [57,89,90,127,228,229]. ADAM12, another myoferlin binding protein normally expressed by myoblasts is required for myoblast fusion and contains a metalloproteinase domain that cleaves type IV collagens [230][231][232].…”