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The concept that lung adenocarcinoma is less related to smoking behavior than lung squamous cell carcinoma may be due to the fact that a considerable number of LAC patients do not have smoking habit. However, this argument may mislead the effect of tobacco smoke on LAC because it ignores the potential effects of environmental smoking that cause second hand smoking in non-smokers. In Taiwan, 70% of female LAC patients would encounter heavy smokers either at home or in working place, suggesting that environmental smoke may have substantial effects than we thought. Transcriptional deregulation at the chromosome 15q25 locus revealed an association between the gene encoding CHRNA5 with lung adenocarcinoma risk. It has been showed that overexpression of the genes encoded in this locus in mice increased the sensitivity to nicotine. In this report, we found that nAChR α5, but neither nAChR α7 or nAChR α9 that have been respectively shown to mediate tumorigenic alterations in lung SCC and breast cancer cells, was differentially expressed between tumor and non-tumor specimens of LAC patient specimens. Knockdown of nAChR α5 in LAC cell lines resulted in decreased cell proliferation rate as well as cell migrating and invasive capabilities. In these nAChR α5-knockdown cells, low dose (10 nM) nicotine was not able to significantly increase cell proliferation and motility, while low dose nicotine enhanced both abilities of cells when nAChR α5 expressed. Colony formation assay indicated that nAChR α5 maintained cell survival and prevent contact inhibition in LAC cells when encountering low serum stress condition. Through molecular analysis, we showed that nAChR α5 positively regulates epithelial-mesenchymal transition factors such as Snail and Slug, and negatively regulates E-cadherin. Animal experiment showed a severely suppressed tumor growth in mice transplanted with LAC cells with nAChR α5 being knocked down, in comparison to mice transplanted with parental cells. These data demonstrated a crucial role of nAChR α5 in low-dose nicotine-dependent regulation of tumorigenesis in LAC. It is, for the first time, a study of mechanism in response to low dose nicotine that implies the regulatory pathway underlying the effect of environmental nicotine. Citation Format: Mong-Lien Lotus Wang, Yi-Fan Hsu, Chih-Hsuan Liu, Cheng-Wen Wu. Nicotinic acetylcholine receptor α5 mediates low-dose nicotine-dependent regulation of tumorigenesis in lung adenocarcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4992. doi:10.1158/1538-7445.AM2015-4992