Shi Dan, Wu Jingjing, Wu Youqile, Lin Xiaojing, Xu Cai, Lian Xuemei
Center for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China.
Department of Nutrition and Food Hygiene, School of Public Health and Management, Chongqing Medical University, Chongqing, China.
Front Oncol. 2021 Feb 23;11:620993. doi: 10.3389/fonc.2021.620993. eCollection 2021.
Epidemiological studies have recently shown that obesity increases lung cancer risk, but the underlying biological connection is unclear. To determine whether high-fat diet (HFD)-induced obesity influences the susceptibility to chemical-induced lung tumorigenesis, a HFD feeding condition was combined with a multi-dose urethane-induced lung tumorigenesis model using C57BL/6J mice. In cell culture models, lung cancer cell lines A549 and H460 were used to investigate the effect of leptin on cell viability and its underlying mechanism of action. The results showed that obesity was induced with a 60 kcal% HFD feeding. Serum leptin levels increased with HFD feeding and further increased in urethane-administered and HFD-fed mice. Compared to the control diet-fed mice, the HFD-fed mice exhibited increased lung tumor burden and typical pro-tumorigenic STAT3 pathway activation in lung tissues after urethane administration. , leptin significantly increased the viability of lung cancer cell lines A549 and H460 in a dose-dependent manner by activation of STAT3, Bcl-2, and cyclin D1. These effects were significantly attenuated when PI3K or mTOR were inhibited by LY294002 or rapamycin, respectively. These results suggested that HFD-induced obesity could promote the development of lung tumorigenesis in C57BL/6J mice, and leptin-mediated activation of the PI3K/Akt/mTOR/STAT3 pathway was likely involved in this mechanism.
流行病学研究最近表明，肥胖会增加肺癌风险，但潜在的生物学联系尚不清楚。为了确定高脂饮食（HFD）诱导的肥胖是否会影响化学诱导的肺癌发生易感性，将HFD喂养条件与使用C57BL/6J小鼠的多剂量尿烷诱导的肺癌发生模型相结合。在细胞培养模型中，使用肺癌细胞系A549和H460来研究瘦素对细胞活力的影响及其潜在作用机制。结果表明，60千卡%的HFD喂养可诱导肥胖。血清瘦素水平随着HFD喂养而升高，在给予尿烷和HFD喂养的小鼠中进一步升高。与对照饮食喂养的小鼠相比，HFD喂养的小鼠在给予尿烷后肺肿瘤负担增加，肺组织中出现典型的促肿瘤STAT3途径激活。此外，瘦素通过激活STAT3、Bcl-2和细胞周期蛋白D1，以剂量依赖的方式显著增加肺癌细胞系A549和H460的活力。当PI3K或mTOR分别被LY294002或雷帕霉素抑制时，这些作用显著减弱。这些结果表明，HFD诱导的肥胖可促进C57BL/6J小鼠肺癌发生的发展，瘦素介导的PI3K/Akt/mTOR/STAT3途径激活可能参与了这一机制。
