Increased chemoresistance via Snail–Raf kinase inhibitor protein signaling in colorectal cancer in response to a nicotine derivative
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Tsai-Yu Lee1,2,3, Chia-Lin Liu4, Yun-Ching Chang5, Shin Nieh5, Yaoh-Shiang Lin6, Shu-Wen Jao3, Su-Feng Chen7, Tsung-Yun Liu1
1Institute of Environmental and Occupational Health Sciences, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
2Division of Colon and Rectum Surgery, Department of Surgery, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei, Taiwan, ROC
3Division of Colon and Rectum Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
4Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC
5Department and Graduate School of Pathology, National Defense Medical Center & Tri-Service General Hospital, Taipei, Taiwan, ROC
6Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC
7Department of Dental Hygiene, China Medical University, Taichung, Taiwan, ROC
Tsung-Yun Liu, e-mail: email@example.com
Shin Nieh, e-mail: firstname.lastname@example.org
Shu-Wen Jao, e-mail: email@example.com
Su-Feng Chen, e-mail: firstname.lastname@example.org
Keywords: nicotine, NNK, chemoresistance, Snail, colorectal cancer
Received: November 17, 2015 Accepted: February 29, 2016 Published: March 14, 2016
A tobacco-specific component, 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK), is a major risk factor for many cancers. Recent reports have demonstrated that NNK exposure may be associated with tumor progression and chemoresistance in certain cancers. However, the underlying NNK-induced mechanism contributing to the aggressiveness of colorectal cancer (CRC) has not been thoroughly studied. In this study, we used HT29 cells treated with NNK to simulate the long-term exposure of cigarette smoke. A comparative analysis was performed to evaluate cell proliferation, migration, and invasion as well as epithelial-mesenchymal transition (EMT) markers and drug-resistance genes expression, cancer stem cell (CSC) properties, and anti-apoptotic activity. Signaling pathways related to chemoresistance were also investigated. As a result, NNK exposure dose-dependently stimulates cell proliferation, enhance abilities of migration and invasion, induce EMT phenomenon, and attenuate apoptosis. Furthermore, NNK exposure also promotes the capabilities of sphere formation, upregulation of Snail, and overexpression of CD133, Nanog, OCT4, and the drug-resistant genes. Knockdown of Snail results in upregulation of Raf kinase inhibitor protein (RKIP), increased apoptosis, reversal of EMT phenomenon, and reducation of expression of CSC markers, all of which contribute to a decrease of chemoresistance. Our study demonstrates a number of related mechanisms that mediate the effect of NNK exposure on increasing CRC therapeutic resistance via the Snail signaling pathway. Targeting Snail may provide a feasible strategy for the treatment of CRC.
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