Fbxw7 haploinsufficiency loses its protection against DNA damage and accelerates MNU-induced gastric carcinogenesis

doi:10.18632/oncotarget.16800

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	Fbxw7 haploinsufficiency loses its protection against DNA damage and accelerates MNU-induced gastric carcinogenesis
	Jiang, Yannan 1; Qi, Xinming2 ; Liu, Xinyu 1; Zhang, Jun 1; Ji, Jun 1; Zhu, Zhenggang 1; Ren, Jin; Yu, Yingyan 1
刊名	ONCOTARGET
	2017-05-16
卷号	8 期号:20 页码:33444-33456
关键词	Fbxw7 knockout mouse N-Methyl-N-nitrosourea gastric cancer DNA damage
ISSN号	1949-2553
DOI	10.18632/oncotarget.16800
文献子类	Article
英文摘要	Fbxw7, a subunit of the SCF E3 ubiquitin ligase, recognizes oncoprotein substrates and leads to their proteasomal degradation. Fbxw7 acts as a tumor suppressor via inducing apoptosis and growth arrest in various kinds of tumors. To clarify the initiating role in gastric carcinogenesis as well as the histologic characterization of tumor in Fbxw7 allele haploinsufficient mice, we generated Fbxw7 heterozygous knockout mice (Fbxw7(+/-)) and treated them with chemical carcinogen N-methyl-N-nitrosourea (MNU) at 5-6 weeks of age. We also treated mouse embryo fibroblasts (MEFs) from Fbxw7(+/-) and Fbxw7(+/+) mice with MNU and examined cell DNA damage via comet assay. The protein expression of Fbxw7 and its substrate c-Myc from mouse tumors, as well as human tumors sampled from six patients, were detected by Western blot. As results, the tumor incidence was obviously higher in Fbxw7(+/-) mice (13/20) than in Fbxw7(+/+) mice (6/20) after 35-week observation. Intestinal metaplasia (P = 0.013) and dysplasia (P = 0.036) were more severe in Fbxw7(+/-) mice than in Fbxw7(+/+) mice. The repair potential of DNA damage was suppressed in MEFs from Fbxw7(+/-) mice after MNU exposure. Increased c-Myc expression was accompanied by decreased Fbxw7 protein expression in tumor tissues from mouse and patients. In conclusion, Fbxw7 haploinsufficiency increased the risk of gastric carcinogenesis induced by MNU, which is associated with the accumulation of DNA damage as well as c-Myc oncoprotein.
资助项目	Chinese National Key Program[2016YFC1303202] ; Chinese National Key Program[2012AA02A504] ; Chinese National Key Program[2012AA02A203] ; National Natural Science Foundation of China[81372644] ; Project of Shanghai Science and Technology Commission[11XD1403600] ; Project of Shanghai Science and Technology Commission[12410706400] ; Innovation Foundation of Translational Medicine of Shanghai Jiao Tong University School of Medicine[15ZH1002] ; Innovation Foundation of Translational Medicine of Shanghai Jiao Tong University School of Medicine[15ZH400] ; Innovation Foundation of Translational Medicine of Shanghai Jiao Tong University School of Medicine[TM201617] ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020339] ; National Science and Technology Major Project[2015ZX09102005]
WOS关键词	FBW7 UBIQUITIN LIGASE ; METHYL-N-NITROSOUREA ; TUMOR-SUPPRESSOR ; F-BOX ; GENOMIC INSTABILITY ; HUMAN CANCER ; STEM-CELLS ; MICE ; PROGRESSION ; FBXW7/HCDC4
WOS研究方向	Oncology ; Cell Biology
语种	英语
出版者	IMPACT JOURNALS LLC
WOS记录号	WOS:000401767700087
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272662]
专题	药物安全性评价中心
通讯作者	Yu, Yingyan
作者单位	1.Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Gastr Neoplasms, Dept Surg,Shanghai Ruijin Hosp,Shanghai Inst Dige, Shanghai 200025, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Jiang, Yannan,Qi, Xinming,Liu, Xinyu,et al. Fbxw7 haploinsufficiency loses its protection against DNA damage and accelerates MNU-induced gastric carcinogenesis[J]. ONCOTARGET,2017,8(20):33444-33456.
APA	Jiang, Yannan.,Qi, Xinming.,Liu, Xinyu.,Zhang, Jun.,Ji, Jun.,...&Yu, Yingyan.(2017).Fbxw7 haploinsufficiency loses its protection against DNA damage and accelerates MNU-induced gastric carcinogenesis.ONCOTARGET,8(20),33444-33456.
MLA	Jiang, Yannan,et al."Fbxw7 haploinsufficiency loses its protection against DNA damage and accelerates MNU-induced gastric carcinogenesis".ONCOTARGET 8.20(2017):33444-33456.