Wang Chunxiao, Niu Wenwen, Chen Hui, Shi Ni, He Dian, Zhang Min, Ge Lihua, Tian Zhenchuan, Qi Moci, Chen Tong, Tang Xiaofei
Division of Oral Pathology, Beijing Institute of Dental Research, Beijing Key Laboratory, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing, China.
Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA.
Oncotarget. 2017 Aug 24;8(43):75065-75075. doi: 10.18632/oncotarget.20506. eCollection 2017 Sep 26.
Nicotine, a tumor promoter in tobacco, can increase Peroxiredoxin (Prx1) and nicotinic acetylcholine receptors (nAChRs) in oral squamous cell carcinoma (OSCC). In the present study, we investigate the effects of nicotine in oral precancerous lesions focusing on apoptosis and nAChR/Prx1 signaling. We detected expression of Prx1, α3nAChR, α7nAChR, phosphorylation of mitogen-activated protein kinases (MAPK) and apoptosis in dysplastic oral keratinocyte (DOK) cells as well as in 4-nitroquinoline 1-oxide (4NQO) or 4NQO + nicotine - induced oral precancerous lesions in Prx1 wild-type (Prx1) and Prx1 knockdown (Prx1) mice. In DOK cells, Prx1 knockdown and blocking α7nAChR activated apoptosis, and nicotine increased the expression of Prx1, α3nAChR and α7nAChR, and inhibited MAPK activation. Moreover, nicotine suppressed apoptosis depending on Prx1 and α7nAChR in DOK cells. In animal bioassay, nicotine and Prx1 promoted growth of 4NQO-induced precancerous lesions in mouse tongue. 4NQO plus nicotine suppressed MAPK activation in Prx1 wild-type mice but not in Prx1 knockdown mice. Our data demonstrate that nicotine inhibits cell apoptosis and promotes the growth of oral precancerous lesions via regulating α7nAChR/Prx1 during carcinogenesis of OSCC.
尼古丁是烟草中的一种肿瘤促进剂，可增加口腔鳞状细胞癌（OSCC）中的过氧化物酶（Prx1）和烟碱型乙酰胆碱受体（nAChRs）。在本研究中，我们聚焦于细胞凋亡和nAChR/Prx1信号传导，研究尼古丁在口腔癌前病变中的作用。我们检测了发育异常的口腔角质形成细胞（DOK）以及4-硝基喹啉1-氧化物（4NQO）或4NQO+尼古丁诱导的Prx1野生型（Prx1）和Prx1基因敲除（Prx1）小鼠口腔癌前病变中Prx1、α3nAChR、α7nAChR的表达、丝裂原活化蛋白激酶（MAPK）的磷酸化和细胞凋亡情况。在DOK细胞中，Prx1基因敲除和阻断α7nAChR可激活细胞凋亡，而尼古丁可增加Prx1、α3nAChR和α7nAChR的表达，并抑制MAPK激活。此外，尼古丁在DOK细胞中可依赖Prx1和α7nAChR抑制细胞凋亡。在动物生物测定中，尼古丁和Prx1可促进小鼠舌部4NQO诱导的癌前病变生长。4NQO加尼古丁可抑制Prx1野生型小鼠中的MAPK激活，但对Prx1基因敲除小鼠无效。我们的数据表明，在OSCC致癌过程中，尼古丁通过调节α7nAChR/Prx1抑制细胞凋亡并促进口腔癌前病变的生长。
