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学科主题: 临床医学
题名:
Estrogen receptor alpha promotes smoking-carcinogen-induced lung carcinogenesis via cytochrome P450 1B1
作者: Li, Ming-Yue1; Liu, Yi1,3; Liu, Li-Zhong4; Kong, Angel W. Y.1; Zhao, Zhili1; Wu, Bin5; Long, Xiang6; Wu, Jun5; Ng, Calvin S. H.1; Wan, Innes Y. P.1; Du, Jing6; Mok, Tony S. K.2; Underwood, Malcolm J.1; Chen, George G.1
关键词: Lung cancer ; Smoking carcinogen NNK ; CYP1B1 ; ER alpha ; ERK/AP1
刊名: JOURNAL OF MOLECULAR MEDICINE-JMM
发表日期: 2015-11-01
DOI: 10.1007/s00109-015-1300-4
卷: 93, 期:11, 页:1221-1233
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Genetics & Heredity ; Medicine, Research & Experimental
研究领域[WOS]: Genetics & Heredity ; Research & Experimental Medicine
关键词[WOS]: TOBACCO-SMOKE ; CIGARETTE-SMOKE ; AP-1 ACTIVITY ; CELL-LINES ; CANCER ; EXPRESSION ; BETA ; GENE ; ADENOCARCINOMA ; MICRORNA-21
英文摘要:

Smoking carcinogen N-nitrosamines such as 4-methylnitrosamino-l-3-pyridyl-butanone (NNK) require metabolic activation to exert their genotoxicity. The first activation step is mainly catalyzed by cytochrome P450 (CYP) family. Estrogen receptor alpha (ER alpha) plays a role in lung pathology. The association between them is unknown. In this study, we explored the relationship and function of CYP1B1 and ER alpha in NNK-induced lung tumorigenesis. CYP1B1 and ER alpha expression was analyzed in human lung cancer tissues and NNK-induced lung tumor of A/J mice. Cell lines NCI-H23 and NCI-H460 were employed to further study the responsible mechanisms using various cellular and molecular approaches. Our in vivo experiments demonstrated that CYP1B1 and ER alpha were over-expressed at the early stage of NNK-induced lung tumorigenesis. Microarray analysis found that ER alpha was involved in the extracellular-signal-regulated kinase (ERK)/MAPK pathway. NNK activated RAS/ERK/AP1 as it remarkably increased the levels of p-ERK, c-Fos, and c-Jun but inhibited multiple negative regulators of Ras/ERK/AP1, Pdcd4, Spry1, Spry2, and Btg2 through up-regulating miR21. Both CYP1B1 siRNA and ERK-specific inhibitor U0126 suppressed NNK-mediated ER alpha up-regulation, suggesting that ER alpha was downstream of CYP1B1 and ERK. ERK inactivation led to the accumulation of CYP1B1, indicating that CYP1B1 was upstream of ERK activation. Inhibition of ERK or ER alpha decreased NNK-induced cell proliferation. Blockage of CYP1B1 or ER alpha induced apoptosis of lung cancer cells. Collectively, NNK-mediated ER alpha induction is via CYP1B1 and ERK and contributes to the lung carcinogenesis. The inhibition of CYP1B1, ERK, or ER alpha may arrest the lung cancer cell growth, implicating a pivotal strategy for the treatment of lung cancer.

Key messages

Smoking carcinogen NNK requires metabolic activation to exert their genotoxicity.

CYP1B1 is the enzyme to catalyze NNK.

NNK activates CYP1B1 and ERK to induce ER alpha.

Inhibition of CYP1B1, ERK, or ER alpha arrests the lung cancer cell growth.

语种: 英语
所属项目编号: CUHK475211 ; 2013.1.104
项目资助者: Research Grants Council of the Hong Kong SAR ; CUHK direct grant
WOS记录号: WOS:000365715100007
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/63903
Appears in Collections:北京大学深圳医院_期刊论文

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作者单位: 1.Guangdong Med Coll, Zhanjiang, Guangdong, Peoples R China
2.Chinese Univ Hong Kong, Prince Wales Hosp, Dept Surg, Shatin, Hong Kong, Peoples R China
3.Chinese Univ Hong Kong, Prince Wales Hosp, Dept Clin Oncol, Shatin, Hong Kong, Peoples R China
4.Shenzhen Univ, Fac Med, Hlth Sci Ctr, Dept Pathophysiol, Shenzhen, Peoples R China
5.Affiliated Hosp Guang Dong Med Coll, Dept Resp Med, Zhanjiang, Guangdong, Peoples R China
6.Peking Univ, Shenzhen Hosp, Shenzhen, Guangdong, Peoples R China

Recommended Citation:
Li, Ming-Yue,Liu, Yi,Liu, Li-Zhong,et al. Estrogen receptor alpha promotes smoking-carcinogen-induced lung carcinogenesis via cytochrome P450 1B1[J]. JOURNAL OF MOLECULAR MEDICINE-JMM,2015,93(11):1221-1233.
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