The Investigation of Cigarette Smoke in Association with Cancer Treatment Resistance

• Main Authors: Tsai-Yu Lee, 李才宇
• Other Authors: Tsung-Yun Liu
• Format: Others
• Language: zh-TW
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/04677833355305192193

博士 === 國立陽明大學 === 環境與職業衛生研究所 === 104 === Cigarette smoke had been proved to be associated with the development of many cancers. Previous reports also indicated that the cancer patients with habit of cigarette smoke had poorer prognosis than non-smoker. However, the underlying cigarette smoke-mediated mechanism contributing to the aggressiveness of cancer has not been thoroughly studied. We used colon and oral cancer cells treated with NNK (nicotine-derived nitrosamine ketone or 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone) to simulate the long-term exposure of cigarette smoke. The comparative analysis was performed to evaluate cell proliferation, migration, and invasion as well as drug-resistance genes expression, anti-apoptotic activity, epithelial-mesenchymal transition (EMT) phenomenon and cancer stem cell (CSC) properties. Signaling pathways related to treatment resistance were also investigated. NNK exposure dose-dependently stimulates cell proliferation, enhances the abilities of migration and invasion, induces EMT phenomenon, and attenuates apoptosis. Furthermore, NNK exposure to cancer cells also promotes the capabilities of sphere formation with upregulation of Snail and overexpression of CD133, Nanog, OCT4, and the drug-resistant genes. Knockdown of Snail results in upregulation of RKIP (Raf kinase inhibitor protein) and increases apoptosis with reversal of EMT phenomenon and reduction of expression of CSC markers, all of which contribute to a decrease of treatment resistance. Our study demonstrates the related mechanisms that mediate the effects of NNK exposure on increasing treatment resistance of colon and oral cancer cells via the Snail signaling pathway. Targeting Snail may provide a feasible strategy for the treatment of cancer.