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Nicotine Promotes Acquisition of Stem Cell and Epithelial-to-Mesenchymal Properties in Head and Neck Squamous Cell Carcinoma

2012; Public Library of Science; Volume: 7; Issue: 12 Linguagem: Inglês

10.1371/journal.pone.0051967

1932-6203

Michael Yu, Alan Kiang, Jessica Wang‐Rodriguez, Elham Rahimy, Martin Haas, Vicky Yu, Lesley G. Ellies, Jing Chen, Jian‐Bing Fan, Kevin T. Brumund, Robert A. Weisman, Weg M. Ongkeko,

Cancer, Stress, Anesthesia, and Immune Response

The ability of nicotine to enhance the malignancy of cancer cells is known; however, the possibility that nicotine could regulate a cancer stem cell phenotype remains to be well-established. In this study we sought to determine whether long-term exposure to nicotine could promote cancer stem cell-like properties in two head and neck squamous cell carcinoma cell lines, UMSCC-10B and HN-1. Nicotine treatment induced epithelial-to-mesenchymal transition (EMT) in both cell lines by repressing E-cadherin expression, and led to the induction of stem cell markers Oct-4, Nanog, CD44 and BMI-1, which was reversed upon ectopic re-expression of E-cadherin. Nicotine-treated cells formed spheres at a higher efficiency than non-treated cells, formed larger tumors when injected into mice, and formed tumors with 4-fold greater efficiency compared to control cells when injected at limiting doses. Consistent with previous literature, nicotine-treated cells demonstrated a greater capacity for survival and also a higher tendency to invade. Comparison of microRNA profiles between nicotine and control cells revealed the upregulation of miR-9, a repressor of E-cadherin, and the downregulation of miR-101, a repressor of EZH2. Taken together, these results suggest that nicotine may play a critical role in the development of tobacco-induced cancers by regulating cancer stem cell characteristics, and that these effects are likely mediated through EMT-promoting, microRNA-mediated pathways. Further characterization of such pathways remains a promising avenue for the understanding and treatment of tobacco-related cancers.