Long-Term Cisplatin Exposure Promotes Methylation of the OCT1 Gene in Human Esophageal Cancer Cells
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ORIGINAL ARTICLE
Long-Term Cisplatin Exposure Promotes Methylation of the OCT1 Gene in Human Esophageal Cancer Cells Rui Lin • Xiaoli Li • Jiansheng Li • Lianfeng Zhang Feng Xu • Yanjun Chu • Jichang Li
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Received: 8 July 2012 / Accepted: 19 September 2012 / Published online: 6 October 2012 Ó Springer Science+Business Media New York 2012
Abstract Background Cisplatin-based chemotherapy is widely used for treatment of a variety of human malignant solid and metastatic tumors, including esophageal cancer. However, the clinical effect of this drug is limited because of intrinsic and acquired resistance to it. Organic cation transporters (OCTs) are important in the cellular uptake of cisplatin. Aim Our objective was to test the hypothesis that cisplatin resistance is associated with alteration of expression of OCTs. Methods Levels of expression of OCTs in paired esophageal cancer and adjacent non-cancerous tissues were examined by use of immunohistochemistry. Results We found that OCT1 silencing impaired cisplatin-mediated apoptosis of esophageal cancer cells. The level of OCT1 mRNA in cisplatin-resistant cells was markedly reduced compared with parental cells. Promoter methylation of OCT1 was induced in cisplatin-resistant cells. Conclusion This study shows that long-term exposure to cisplatin promotes methylation of the OCT1 gene in human
R. Lin J. Li L. Zhang F. Xu Y. Chu J. Li Department of Gastroenterology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China R. Lin X. Li (&) J. Li L. Zhang F. Xu Y. Chu J. Li Institute of Clinical Medical Research of Universities in Henan Province, 1 East Jianshe Road, Zhengzhou 450052, Henan, People’s Republic of China e-mail: [email protected] X. Li Department of Gerontology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
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esophageal cancer cells, which in turn results in cisplatin resistance. Keywords OCT1 Cisplatin Hypermethylation Esophageal cancer
Introduction Esophageal cancer is the ninth most common malignancy and the sixth leading cause of cancer mortality in the world [1]. Although surgical resection is the best treatment option for locoregional esophageal cancer, nearly 50 % of patients diagnosed with esophageal cancer already have disseminated tumor cells. Chemotherapy alone or in combination with radiotherapy has improved prognosis for esophageal cancer patients [2, 3]. Cisplatin-based chemotherapy is widely used for treatment of esophageal cancer. Unfortunately, development of cisplatin resistance by cancer cells is a major obstacle to successful treatment, and the underlying mechanism of such resistance is not fully understood. Several mechanisms of cisplatin resistance, for example diminished accumulation of cisplatin in cancer cells, have been postulated. DNA methylation of some genes also has been found to be associated with cisplatin resistance [4, 5]. It was recently found that the DNA methylation is a frequent event in cells that are chronically exposed to cisplatin, and that methyla
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