Overexpression of MCPH 1 inhibits uncontrolled cell growth by promoting cell apoptosis and arresting the cell cycle in S and G 2 / M phase in lung cancer cells

Microcephalin (MCPH1/BRIT1) is a large nuclear protein that is involved in the early cellular response to DNA damage, the expression of which is reduced in a variety of types of human tumors. A recent study by our group demonstrated that MCPH1 expression is markedly decreased in lung cancer. However, it remains unclear whether inducing the expression of MCPH1 may ameliorate lung cancer, and, if so, which mechanisms underlie this process. The results of the present study demonstrated that MCPH1 expression was downregulated in lung cancer tissues compared with that in normal lung tissues. Furthermore, MCPH1 overexpression in A549 non-small cell lung carcinoma cells, successfully inhibited cell proliferation via arrest of the cell cycle in the S and G2/M phases. In addition, MCPH1 overexpression promoted cell apoptosis, in association with a significant increase in the quantities of Bax and active caspase-3, as well as a decrease in the level of Bcl-2. In conclusion the present results indicated that MCPH1 is involved in the regulation of apoptosis and entry into mitosis, suggesting that MCPH1 may function as a tumor suppressor and that it may be important in the pathogenesis of lung cancer. Introduction Lung cancer is one of the most common types of malignancy (1). Worldwide, it remains the leading cause of cancer-related mortality in males and females, and was responsible for 1.56 million deaths annually in 2012 (2). Conventional treatments for lung cancer include surgery, chemotherapy and radiotherapy (3). Although these treatments produce marked benefits in patients with lung cancer, they have a range of side-effects, such as hair loss, immunosuppression, and nausea and vomiting. In addition, the prognosis of advanced lung cancer is very poor, and the five‐year survival is ~16.8% in the US and lower still in the developing world (4,5). However, gene therapy, which involves the delivery of therapeutic DNA into a patient's cells, has been investigated as a novel treatment for lung cancer in a number of clinical trials. For example, Morgan et al (6) successfully treated metastatic melanoma in two patients by using killer T cells that had been genetically retargeted to attack cancer cells. Strategies for gene therapy include induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine-based therapy, vaccination-based approaches and adoptive transfer of modified immune cells (7). MCPH1, also termed BRIT1 (BRCT-repeat inhibitor of hTERT expression), encodes the MCPH1 protein that contains three BRCT domains: one in the N-terminus and two in the C-terminus. Besides MCPH1, numerous other proteins that are involved in tumor suppression and the DNA damage response, such as BRCA1, BRCA2, 53BP1, XRCC1, Rad9, NBS1 and DNA polymerase λ, also contain BRCT domains (8). Previous studies have demonstrated that BRCT-containing MCPH1 may be important in maintaining genome stability, which requires the activation of cell cycle checkpoints and the repair of damaged DNA (9,10). Indeed, MCPH1 knockdown reduces the expression of BRCA1 and the checkpoint kinase, Chk1, in addition to NBS1 phosphorylation, resulting in intra-S and G2/M checkpoint loss (9). Overexpression of MCPH1 inhibits uncontrolled cell growth by promoting cell apoptosis and arresting the cell cycle in S and G2/M phase in lung cancer cells LIMIN ZHOU1,2*, YANJIE BAI1,3*, YANXI LI4, XUELIANG LIU5, TAO TAN1,2, SHASHA MENG1,2, WENTING HE1,2, XIAOBIN WU1,2 and ZHIFANG DONG1,2 1Ministry of Education Key Laboratory of Child Development and Disorders; 2Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014; 3College of Stomatology, Chongqing Medical University, Chongqing 400015; Departments of 4Dermatology and 5Otolaryngology, The Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, P.R. China Received September 30, 2014; Accepted June 25, 2015 DOI: 10.3892/ol.2015. 3857 Correspondence to: Mr. Xiaobin Wu or Professor Zhifang Dong, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, 136 Zhongshan Er Road, Yuzhong, Chongqing 400014, P.R. China E-mail: wuxiaobin1999@163.com E-mail: zfdong@cqmu.edu. cn *Contributed equally