Expression of Nicotinic Acetylcholine Receptor Subunit Genes in Non–Small-Cell Lung Cancer Reveals Differences between Smokers and Nonsmokers

Abstract

Nicotine and its derivatives, by binding to nicotinic acetylcholine receptors (nAChR) on bronchial epithelial cells, can regulate cellular proliferation and apoptosis via activating the Akt pathway. Delineation of nAChR subtypes in non-small-cell lung cancers (NSCLC) may provide information for prevention or therapeutic targeting. Expression of nAChR subunit genes in 66 resected primary NSCLCs, 7 histologically non-involved lung tissues, 13 NSCLC cell lines, and 6 human bronchial epithelial cell lines (HBEC) was analyzed with quantitative PCR and microarray analysis. Five nonmalignant HBECs were exposed to nicotine in vitro to study the variation of nAChR subunit gene expression with nicotine exposure and removal. NSCLCs from nonsmokers showed higher expression of nAChR A6 (P < 0.001) and B3 (P = 0.007) subunit genes than those from smokers, adjusted for gender. In addition, nAChR A4 (P < 0.001) and B4 (P = 0.029) subunit gene expression showed significant difference between NSCLCs and normal lung. Using Affymetrix GeneChip U133 Sets, 65 differentially expressed genes associated with NSCLC nonsmoking nAChR A6B3 phenotype were identified, which gave high sensitivity and specificity of prediction. nAChR A1, A5, and A7 showed significant reversible changes in expression levels in HBECs upon nicotine exposure. We conclude that between NSCLCs from smokers and nonsmokers, different nAChR subunit gene expression patterns were found, and a 65-gene expression signature was associated with nonsmoking nAChR A6B3 expression. Finally, nicotine exposure in HBECs resulted in reversible differences in nAChR subunit gene expression. These results further implicate nicotine in bronchial carcinogenesis and suggest targeting nAChRs for prevention and therapy in lung cancer. [Cancer Res 2007;67(10):4638-47]

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…These nAChR receptors are expressed in human and rodent bronchial epithelial cells, 104 and in non-small-cell lung cancers. 105 We do not know at this time whether polymorphisms in this cluster can directly increase the sensitivity of the target tissues to tobacco smoke and/or nicotine toxicity. 106 Besides the option that variants in the CHRNA5-CHRNA3-CHRNB4 loci increase LC risk solely due to involvement in increased smoking, it is also possible that genetic variants in nAChRs directly influence mechanisms of lung carcinogenesis, without mediation by smoking phenotypes.…”

Synthesis of 8-Hydroxyquinoline Derivatives as Novel Antitumor Agents

“…Athymic nude mice tumorxenograft experiments with subcutaneous Hep3B tumor confirmed its in vivo antitumor activity for abolishing the growth of the tumor at a dose of 10 mg/kg/day on day 9 when administrated intraperitoneally with no observable toxicity from the vital organs at histological level. To identify the most involved molecular pathways of the drug actions, a preliminary cDNA microarray analysis was performed in the Genome Research Centre of the University of Hong Kong using the Human Genome U133 Plus 2.0 arrays (Affymetrix) as previously described 28 to identify the differentially expressed genes in cancer cells after the treatment with compound 3. Total RNA was extracted from the vehicle control and the esophageal cancer cell line KYSE150 treated with 8.5 μg/mL of compound 3 for 48 h with reference to the MTS 50 value (6.25− 12.5 μg/mL).…”

ID1 Facilitates the Growth and Metastasis of Non-Small Cell Lung Cancer in Response to Nicotinic Acetylcholine Receptor and Epidermal Growth Factor Receptor Signaling

“…Indeed, EGFR overexpression is observed in 62% of NSCLC cases and is correlated with poor prognosis (21,38,54). Studies in recent years have also shown polymorphisms in nAChR genes that correlate with NSCLC in smokers (25,37,51). Since primary cells from the lung as well as lung cancer cells can proliferate in response to both nAChR and EGFR signaling, it is probable that there might be common mediators of these signals in smokers and nonsmokers.…”