Abstract：
Constituents of cigarette smoke are known to be carcinogens. Additionally, there is mounting evidence that the liver is an organ susceptible to tobacco carcinogenicity. Nicotine, the primary constituent of tobacco, plays a role in cancer progression. In our previous study, it was found that nicotine enhances the proliferation of a human normal fetal hepatic (WRL68) cell due to the activation of p53 mutation at Ser249 (p53-RS)/STAT1/CCND1 signaling pathway. Here, we further elucidated the mechanism of regulating this pathway. Firstly, dose-dependent increase of SETDB1 protein level in WRL68 cells upon exposure to nicotine (1.25, 2.5, and 5 μM), significantly enhanced cellular proliferation. In addition, the upregulation of SETDB1 protein was necessary for the nuclear translocation of p53-RS to establish a ternary complex with STAT1 and SETDB1, which facilitated p53-RS di-methylation at K370 (p53-RS/K370me2). After that, the activation of CCND1/PI3K/AKT pathway was initiated when STAT1 stability was enhanced by p53-RS/K370me2, ultimately resulting in cell proliferation. Altogether, the study revealed that the increase in SETDB1 expression could potentially have a significant impact on the activation of CCND1/PI3K/AKT pathway through p53-RS/K370me2, leading to the proliferation of WRL68 cells induced by nicotine, which could contribute to hepatocellular carcinoma for smokers. Besides, the results of this study provided a foundation for the development of anticancer therapies for cancers associated with tobacco use.
摘要：
香烟烟雾的成分已知是致癌物。此外,越来越多的证据表明，肝脏是烟草致癌性的一个器官。尼古丁,烟草的主要成分，在癌症进展中起作用。在我们之前的研究中,研究发现,尼古丁通过激活Ser249(p53-RS)/STAT1/CCND1信号通路的p53突变,增强人正常胎肝(WRL68)细胞的增殖.这里,我们进一步阐明了调节该途径的机制。首先,暴露于尼古丁后，WRL68细胞中SETDB1蛋白水平的剂量依赖性增加（1.25、2.5和5μM），细胞增殖显著增强。此外,SETDB1蛋白的上调是p53-RS核易位与STAT1和SETDB1建立三元复合物所必需的,这促进了p53-RS在K370的二甲基化(p53-RS/K370me2).之后,当p53-RS/K370me2增强STAT1稳定性时,CCND1/PI3K/AKT通路激活,最终导致细胞增殖.总之,该研究表明，SETDB1表达的增加可能通过p53-RS/K370me2对CCND1/PI3K/AKT通路的激活产生重大影响，导致尼古丁诱导的WRL68细胞增殖，这可能导致吸烟者的肝细胞癌。此外,这项研究的结果为开发与烟草相关的癌症的抗癌疗法提供了基础。
