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.

Nicotine enhances invasion and metastasis of human colorectal cancer cells through the nicotinic acetylcholine receptor downstream p38 MAPK signaling pathway

“…In mouse tumor transplantation models, nicotine increases the growth and metastasis of various tumor cells including the liver metastasis of orthotopically implanted pancreatic adenocarcinoma cells, subcutaneously injected head and neck squamous cell carcinoma cell lines and NNK-induced lung tumors (15)(16)(17). In particular, Wei et al showed that nicotine enhanced colon cancer cell migration through activation of α7 nicotinic acetylcholine receptor (nAChR) and induction of E-cadherin (12).…”

Nicotine-Mediated Cell Proliferation and Tumor Progression in Smoking-Related Cancers

“…It has also been proposed that nicotine and nAChRs can contribute to stem-like functions of tumor initiating cells, by inducing embryonic stem cell transcription factors including Oct4 and Nanog (82, 83). Nicotine treatment also enhanced the expression of CD44 and BMI-1, and promoted the sphere formation capacity of squamous cell carcinoma cells (83).…”

“…Nicotine treatment also enhanced the expression of CD44 and BMI-1, and promoted the sphere formation capacity of squamous cell carcinoma cells (83). Similar results have been reported in oral epithelial cells as well, supporting the contention that exposure to nicotine can promote EMT as well as stemness (82).…”

Revisiting Chaos Theorem to Understand the Nature of miRNAs in Response to Drugs of Abuse

“…miR‐29b was downregulated in response to alcohol (Qi et al, ) and stimulants (Eipper–Mains et al, 2011) and it was also reported to be upregulated in response to alcohol (Li et al, ), anesthetics (O'Connor et al, 2013), cannabinoids (Chandra et al, ) and opioids (Hu et al, ). Also, miR‐9 was upregulated in alcohol (Wang et al, ; Yadav et al, ; Balaraman et al, ), tobacco/nicotine (Yu et al, ) (Bala et al, ), opioids (Hu et al, ) and stimulants (Tatro et al, ; Varma and Kovtun, ) studies, and was downregulated in other alcohol studies (Balaraman et al, ; Balaraman et al, ; Sathyan et al, 2007; Qi et al, ). In addition, miR‐122 was downregulated in some alcohol studies (Bala et al, ; Li et al, ; Ignacio et al, ; Meng et al, 2012), while it was upregulated in other alcohol (Zhang et al, ; Bala et al, ; Dippold et al, ; Hou et al, ) and opioid (Qiu et al, ) studies.…”