title: α5 Nicotinic acetylcholine receptor mediates nicotine-induced HIF-1α and VEGF expression in non-small cell lung cancer.
abstract: By binding to nicotinic acetylcholine receptors (nAChRs), nicotine induces the proliferation and apoptosis of non-small cell lung cancer (NSCLC). Previous studies have indicated that α5-nAChR is highly associated with lung cancer risk and nicotine dependence. However, the mechanisms through which α5-nAChRs may influence lung carcinogenesis are far from clear. In the present study, we investigated the roles of α5-nAChR in the nicotine-induced expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Immunohistochemistry was used to detect the expression of α5-nAChR and HIF-1α in 60 specimens of lung cancer and para-carcinoma tissue. The correlations between the expression levels of α5-nAChR and HIF-1α and other clinicopathological data were analyzed. In a cell line that highly expressed α5-nAChR, the loss of α5-nAChR function by siRNA was used to study whether α5-nAChR is involved in the nicotine-induced expression of HIF-1α and VEGF through the activation of the ERK1/2 and PI3K/Akt signaling pathways. Cell growth was detected using the cell counting kit-8 (CCK-8). α5-nAChR (78.3%) and HIF-1α (88.3%) were both overexpressed in NSCLC, and their expression levels were found to be correlated with each other (P<0.05). In the A549 cell line, α5-nAChR and HIF-1α were found to be expressed under normal conditions, and their expression levels were significantly increased in response to nicotine treatment. The silencing of α5-nAChR significantly inhibited the nicotine-induced cell proliferation compared with the control group and attenuated the nicotine-induced upregulation of HIF-1α and VEGF, and these effects required the cooperation of the ERK1/2 and PI3K/Akt signaling pathways. These results show that the α5-nAChR/HIF-1α/VEGF axis is involved in nicotine-induced tumor cell proliferation, which suggests that α5-nAChR may serve as a potential anticancer target in nicotine-associated lung cancer.
authors.affiliation: Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Ma
authors.affiliation: Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zu
authors.affiliation: Institute of Infectious Diseases, 302 Military Hospital, Beijing 100039, China.
authors.forename: Ruisheng
authors.initials: R
authors.lastname: Li
authors.affiliation: Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China.
authors.forename: Dongjie
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Department of Dermatology, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Dang
authors.affiliation: Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China.
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000633:toxicity*; D011978:Receptors, Nicotinic / Q000378:metabolism / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011978:Receptors, Nicotinic; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C577601:nicotinic receptor alpha5 subunit, human; D009538:Nicotine
keywords: HIF-1α; Nicotine; Non-small cell lung cancer; VEGF; α5-nAChR