Abstract
Lung cancer is the leading cause of cancer-related deaths in the world. Achaete-scute complex homolog-1 (Ascl1) is a member of the basic helix-loop-helix (bHLH) transcription factor family that has multiple functions in the normal and neoplastic lung such as the regulation of neuroendocrine differentiation, prevention of apoptosis and promotion of tumor–initiating cells. We now show that Ascl1 directly regulates matrix metalloproteinase-7 (MMP-7) and O(6)-methylguanine-DNA methyltransferase (MGMT). Loss- and gain-of-function experiments in human bronchial epithelial and lung carcinoma cell lines revealed that Ascl1, MMP-7 and MGMT are able to protect cells from the tobacco-specific nitrosamine NNK-induced DNA damage and the alkylating agent cisplatin-induced apoptosis. We also examined the role of Ascl1 in NNK-induced lung tumorigenesis in vivo. Using transgenic mice which constitutively expressed human Ascl1 in airway lining cells, we found that there was a delay in lung tumorigenesis. We conclude that Ascl1 potentially enhances DNA repair through activation of MMP-7 and MGMT which may impact lung carcinogenesis and chemoresistance. The study has uncovered a novel and unexpected function of Ascl1 which will contribute to better understanding of lung carcinogenesis and the broad implications of transcription factors in tobacco-related carcinogenesis.
Highlights
Lung cancer is the leading cause of cancer-related deaths in the world [1,2]
The results suggest that activation of matrix metalloproteinase-7 (MMP-7) and methylguanine-DNA methyltransferase (MGMT) by Achaete-scute complex homologue-1 (Ascl1) may contribute to a delay in tobacco-related lung carcinogenesis in mice
MGMT is expressed in human airways and small cell lung cancer (SCLC) We investigated the expression of MGMT in human lung by IHC in 14 specimens of normal airways and 16 lung NE cancers, including 15 SCLCs and one large cell NE lung carcinoma
Summary
Lung cancer is the leading cause of cancer-related deaths in the world [1,2]. It is estimated that there will be nearly 226,160 new cases and 160,340 deaths from lung cancer in the United States in the year 2012 [3]. The major clinical categories are non small-cell lung cancer (NSCLC), which represents the majority and small cell lung cancer (SCLC). Based on neuroendocrine (NE) features, lung cancers can be divided into NE and non-NE tumors. Up to 25–30% of lung cancers may have NE features, which include the prototypic NE cancer SCLC [4,5]. Ascl is essential for NE cell development and differentiation in the lung and SCLC [6,7]. Constitutive expression of Ascl in mouse airway epithelium promotes proliferation and resistance to apoptosis in non-NE cells, resulting in potentially premalignat lesions called bronchiolization of the alveoli (BOA) [8,9]. When MMP-7 was expressed in human lung cancer or immortalized airway epithelial cells, it enhanced growth and migration. One of the differentially expressed genes in the cells was O(6)-methylguanine-DNA methyltransferase (MGMT) [11]
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