title: Nicotine promotes acquisition of stem cell and epithelial-to-mesenchymal properties in head and neck squamous cell carcinoma.
abstract: 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.
authors.affiliation: Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California San Diego, La Jolla, CA, USA.
authors.forename: Michael Andrew
authors.initials: MA
authors.lastname: Yu
authors.forename: Alan
authors.initials: A
authors.lastname: Kiang
authors.forename: Jessica
authors.initials: J
authors.lastname: Wang-Rodriguez
authors.forename: Elham
authors.initials: E
authors.lastname: Rahimy
authors.forename: Martin
authors.initials: M
authors.lastname: Haas
authors.forename: Vicky
authors.initials: V
authors.lastname: Yu
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Ellies
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Brumund
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weisman
authors.forename: Weg M
authors.initials: WM
authors.lastname: Ongkeko
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D035683:MicroRNAs; D018722:Nicotinic Agonists; D012333:RNA, Messenger; D009538:Nicotine