Long-term 4-Methylnitrosamino-1-3-pyridyl-1-butanone(NNK) Exposure Enhances Anti-apoptotic Properties via Snail Signaling Pathway in Head and Neck Cancer Squamous Cell Carcinoma

• Main Authors: Yi-Han Zeng, 曾嶧涵
• Other Authors: Prof. Shin Nieh
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/92407556125922132184

碩士 === 國防醫學院 === 病理及寄生蟲學研究所 === 101 === Aim: Cigarette smoking with the tobacco-specific components of 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK) becomes one of the major risk factors in the carcinogenesis of many cancers, including head and neck squamous cell carcinoma (HNSCC). Recent studies also suggest that long-term NNK exposure also involved in progression of HNSCC. However, the underlying nicotine-mediated mechanism (s) in regulating cancer stem cell (CSC) and anti-apoptotic properties in HNSCC during tumor progression still remains unclear. Methods and Results: We used SCC-25 and Fadu cells with LT-NNK treatment for three months as study groups. A comparative analysis was performed between the control and LT-NNK cells focusing on the evaluation of proliferation, migration and invasion abilities, the expression of epithelial–mesenchymal transition (EMT)-associated markers, drug-resistance-related genes, CSC, and anti-apoptotic properties. As a result, LT-NNK stimulates cell proliferation in a dose dependent manner and also induces obvious morphological alterations showing EMT phenomenon with changes of representative markers and attenuates apoptosis in addition to an enhancement of migration and invasion. Moreover, LT-NNK also promotes the sphere-forming ability and expression of the drug resistant genes, ABCG2 and MDR1 in addition to upregulation of Snail. Knockdown of Snail or administration of anti-alpha 7 nicotinic acetylcholine receptor increases apoptosis, along with upregulation of RKIP confirming Snail-RKIP signaling pathway. Conclusion: Our data demonstrated that the present study is the first to demonstrate the critical role of LT-NNK exposure of HNSCC responsible for the enhancement of anti-apoptosis and therapeutic resistance via Snail- RKIP signaling pathway. These findings may also provide that administration of anti-alpha 7 nicotinic acetylcholine receptor rather than targeting Snail as a feasible and rational method for the treatment of HNSCC.