Abstract
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.
Highlights
Esophageal cancer is the sixth leading cause of cancer-related mortality in the world [1,2,3], incurring more than 456,000 new cases per year worldwide [3], and its prognosis remains poor [2]
We found that Na+/Ca2+ exchanger 1 (NCX1) expression was significantly higher in esophageal squamous cell carcinoma (ESCC) primary tissues compared to the noncancerous tissues and was overexpressed in tumor samples from the smoking patients
After immunohistochemistry analysis of NCX1 proteins on 79 biopsy samples of ESCC and their paired noncancerous tissues, we found that the proportion of NCX1 positive cells was significantly higher in ESCC tissues compared with noncancerous tissues (Figure 1A and 1D)
Summary
Esophageal cancer is the sixth leading cause of cancer-related mortality in the world [1,2,3], incurring more than 456,000 new cases per year worldwide [3], and its prognosis remains poor [2]. Cigarette smoking is a major environmental risk factor for mortality www.impactjournals.com/oncotarget of many cancers, including lung cancer, esophageal cancer, liver cancer, gastric cancer and so on [11]. The risk of esophageal cancer has been reported to correlate with the number of cigarettes smoked per day and the duration of smoking. Cigarette smoking is the most consistent environmental risk factor for ESCC [1, 10], the cellular and molecular mechanisms by which tobacco carcinogens induce ESCC remain poorly understood to date
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