Role of SIRT1 in Lung Cancer Prevention by Beta-Cryptoxanthin

SIRT1 在β-隐黄质预防肺癌中的作用

基本信息

批准号：
8819111
负责人：
XIANG-DONG WANG
金额：
$ 16.42万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-06 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8819111
关键词：
A/J Mouse Animals Apoptosis Biological Process Blood Cancer Model Carcinogens Carotenoids Chemopreventive Agent Chronic Obstructive Airway Disease Data Data Analyses Development Diet Dietary Component Dietary intake Disease Down-Regulation Environmental Risk Factor Epigenetic Process Goals Hand Health Histone Deacetylase Inflammation Investigation Knowledge Lung Lung Neoplasms Lung diseases Malignant neoplasm of lung Mediating Metabolism Molecular Molecular Target Mouse Strains Mus Nicotine Pathogenesis Patients Play Point Mutation Population Preventive Preventive Intervention Proteins Pulmonary Emphysema Recruitment Activity Reporting Research Research Personnel Risk Role Signal Pathway Smoke Smokeless Tobacco Smoker Time Tobacco smoke Tobacco smoking Tumor Promoters Tumor Promotion Tumor Suppressor Proteins Up-Regulation Work Xanthophylls base beta-cryptoxanthin cancer risk cigarette smoking cohort cryptoxanthin environmental tobacco smoke exposure evidence base experience fruits and vegetables immune function lung cancer prevention lung carcinogenesis lung tumorigenesis mouse model novel prevent protective effect tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Lung cancer and chronic obstructive pulmonary disease (COPD) share a strong environmental risk factor (cigarette smoke exposure) and the presence of COPD increases the risk of developing lung cancer up to 4.5 times. Sirtuin 1 (SIRT1), a NAD+-dependent protein/histone deacetylase, has been implicated as a key regulator of metabolism, inflammation, immune function, apoptosis, and tumor development. It has been reported that SIRT1 levels were reduced in smokers and emphysema/COPD patients as well as in animals exposed to smoke. However, the role of SIRT1 in the pathogenesis of lung cancer, specifically, on tumor promotion and progression has not been explored. This information is greatly needed in the highlighting of SIRT1 with dual functions in tumor promoter and tumor suppressor. There are no dietary components and pharmacological agents so far that have convincingly been shown to prevent/alter the progress of lung cancer. This emphasizes the great need for the development of new dietary prevention/intervention agents against this devastating disease. A primary data analysis pooled from seven large well-implemented cohorts showed that increased dietary intake or higher blood levels of one specific xanthophylls carotenoid, b- cryptoxanthin (BCX), is strongly associated with a reduced risk of lung cancer in current smokers. It is not clear what molecular mechanism(s) is involved in BCX action, as a unique biological function, against lung cancer risk. We hypothesize that the down-regulation of SIRT1 is a major mechanism involved in the pathogenesis of the lung cancer promotion by cigarette smoke/nicotine, whereas BCX targets SIRT1 signaling pathway as its chemopreventive action. This hypothesis has been based on our recent findings that nicotine, the main addictive component of tobacco smoke, markedly reduced lung SIRT1 levels accompanying with emphysema and increased both multiplicity and volume of lung tumors in the A/J lung cancer mouse model. Importantly, BCX treatment restored nicotine-reduced lung SIRT1 protein to normal levels and inhibited both nicotine-induced emphysema and nicotine-promoted lung tumor development. We propose two specific aims: 1) Explore the role of SIRT1 signaling pathway in pathogenesis of smoke/nicotine- promoted lung cancer development; and 2) Determine the ability of BCX to modulate SIRT1 signaling pathway as a unique mechanism for prevention of lung cancer development. The investigation of the role of SIRT1 in lung diseases offers novel opportunities to increase our understanding of mechanisms involved in the pathogenesis of COPD and lung cancer. By demonstrating that dietary BCX is effective in targeting the SIRT1 signaling pathway and inhibiting COPD and lung carcinogenesis, this research will open a new prevention/intervention avenue of BCX to reduce lung cancer risk.

描述（由申请人提供）：肺癌和慢性阻塞性肺疾病（COPD）具有强大的环境风险因素（烟烟暴露），并且COPD的存在增加了患肺癌的风险高达4.5倍。 SIRTUIN 1（SIRT1）是NAD+依赖性蛋白/组蛋白脱乙酰基酶，已与代谢，炎症，免疫功能，凋亡和肿瘤发育的关键调节剂有关。据报道，吸烟者和肺气肿/COPD患者以及暴露于烟雾的动物中SIRT1水平降低。然而，尚未探索SIRT1在肺癌发病机理中的作用，特别是尚未探索肿瘤促进和进展。在肿瘤启动子和肿瘤抑制子中具有双重功能的SIRT1突出显示时，非常需要此信息。到目前为止，还没有饮食成分和药理学剂令人信服地证明可以防止/改变肺癌的进展。这强调了开发新的饮食预防/干预剂防止这种毁灭性疾病的巨大需求。从七个大型实施队列中汇集的主要数据分析表明，饮食摄入量增加或一种特定的黄质类胡萝卜素（B-Cryptoxanthin（BCX））的血液水平升高，与当前吸烟者中肺癌的风险降低密切相关。尚不清楚BCX作用中哪种分子机制是针对肺癌风险的独特生物学功能。我们假设SIRT1的下调是通过香烟烟雾/尼古丁促进肺癌的发病机理的主要机制，而BCX靶向SIRT1信号通路作为其化学预防作用。这一假设是基于我们最近的发现，即尼古丁是烟草烟雾的主要成瘾成分，显着降低了伴有肺气肿的肺SIRT1水平，并增加了A/J肺癌小鼠模型中肺肿瘤的多重性和体积。重要的是，BCX治疗将尼古丁还原的肺SIRT1蛋白恢复到正常水平，并抑制尼古丁诱导的肺气肿和尼古丁促进的肺肿瘤发育。我们提出了两个具体的目的：1）探索SIRT1信号通路在烟/尼古丁促进肺癌发育中的发病机理中的作用； 2）确定BCX调节SIRT1信号通路作为预防肺癌发展的独特机制的能力。对SIRT1在肺部疾病中的作用的研究提供了新的机会，以增加我们对COPD和肺癌发病机理的理解。通过证明饮食BCX可以有效地靶向SIRT1信号通路并抑制COPD和肺癌发生，这项研究将开放BCX的新预防/干预途径，以降低肺癌的风险。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

β-Cryptoxanthin Attenuates Cigarette-Smoke-Induced Lung Lesions in the Absence of Carotenoid Cleavage Enzymes (BCO1/BCO2) in Mice.

DOI：
10.3390/molecules28031383
发表时间：
2023-02-01
期刊：
MOLECULES
影响因子：
4.6
作者：
Chiaverelli, Rachel A. A.;Hu, Kang-Quan;Liu, Chun;Lim, Ji Ye;Daniels, Michael S. S.;Xia, Hui;Mein, Jonathan;von Lintig, Johannes;Wang, Xiang-Dong
通讯作者：
Wang, Xiang-Dong

Isocaloric Pair-Fed High-Carbohydrate Diet Induced More Hepatic Steatosis and Inflammation than High-Fat Diet Mediated by miR-34a/SIRT1 Axis in Mice.

DOI：
10.1038/srep16774
发表时间：
2015-11-26
期刊：
Scientific reports
影响因子：
4.6
作者：
Li X;Lian F;Liu C;Hu KQ;Wang XD
通讯作者：
Wang XD

Dietary lycopene attenuates cigarette smoke-promoted nonalcoholic steatohepatitis by preventing suppression of antioxidant enzymes in ferrets.

DOI：
10.1016/j.jnutbio.2021.108596
发表时间：
2021-05
期刊：
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
影响因子：
5.6
作者：
Rakic, Jelena Mustra;Liu, Chun;Veeramachaneni, Sudipta;Wu, Dayong;Paul, Ligi;Ausman, Lynne M.;Wang, Xiang-Dong
通讯作者：
Wang, Xiang-Dong

Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice.