Essential role of Na+/Ca2+ exchanger 1 in smoking-induced growth and migration of esophageal squamous cell carcinoma
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Jiexia Wen1,*, Yan Pang1,*, Tao Zhou2, Ximing Qi1, Min Zhao4, Bin Xuan2, Xiangcai Meng2, Yunsheng Guo2, Qingbin Liu2, Huagang Liang5, Yang Li1, Hui Dong1,3, Yimin Wang1,2
1Department of Central Laboratory, First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
2Department of General Surgery, First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
3Department of Medicine, University of California, San Diego, California, USA
4Department of Pathology, First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
5Department of Thoracic Surgery, First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, Hebei, China
*These authors equally contributed to this work
Yimin Wang, email: [email protected]
Hui Dong, email: [email protected]
Keywords: Na+/Ca2+ exchanger 1, calcium signaling, cigarette smoking, esophageal squamous cell carcinoma, tumorigenesis
Received: April 23, 2016 Accepted: August 24, 2016 Published: August 30, 2016
Tobacco-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a major environmental risk factor for the pathogenesis of human esophageal squamous cell carcinoma (ESCC). However, the molecular mechanisms by which tobacco induces ESCC are not well understood. Na+/Ca2+ exchanger 1 (NCX1) is a plasma membrane transporter protein that plays an essential role in maintaining cytosolic Ca2+ ([Ca2+]cyt) homeostasis under physiological conditions and is implicated in tumorigenesis as well. In this study, we found that NCX1 expression was significantly higher in ESCC primary tissues compared to the noncancerous tissues and was overexpressed in tumor samples from the smoking patients. The expression of NCX1 proteins was also significantly higher in human ESCC cell lines compared to normal esophageal epithelial cell line. Moreover, NNK potentiated the [Ca2+]cyt signaling induced by removal of extracellular Na+, which was abolished by KB-R7943 or SN-6. NNK dose-dependently promoted proliferation and migration of human ESCC cells induced by NCX1 activation. Therefore, NCX1 expression correlates with the smoking status of ESCC patients, and NNK activates the Ca2+ entry mode of NCX1 in ESCC cells, leading to cell proliferation and migration. Our findings suggest NCX1 protein is a novel potential target for ESCC therapy.
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