NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas

doi:10.1053/j.gastro.2015.01.033

科研成果详情

题名	NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas
作者	Chen, Nai-Ming 1; Singh, Garima 3; Koenig, Alexander 1,4; Liou, Geou-Yarh 5; Storz, Peter 5; Zhang, Jin-San4,6; Regul, Lisanne 3; Nagarajan, Sankari 2; Kühnemuth, Benjamin 3; Johnsen, Steven A.2; Hebrok, Matthias 7; Siveke, Jens 8; Billadeau, Daniel D.4; Ellenrieder, Volker 1; Hessmann, Elisabeth 1
发表日期	2015-05
发表期刊	GASTROENTEROLOGY 影响因子和分区
语种	英语
原始文献类型	Article
关键词	Signal Transduction Mouse Model Gene Regulation ChIP
其他关键词	EPIDERMAL-GROWTH-FACTOR ; K-RAS ; FACTOR RECEPTOR ; ONCOGENIC KRAS ; CANCER-CELLS ; C-MYC ; EXPRESSION ; MICE ; INFLAMMATION ; PROGRESSION
摘要	BACKGROUND & AIMS: Oncogenic mutations in KRAS contribute to the development of pancreatic ductal adenocarcinoma, but are not sufficient to initiate carcinogenesis. Secondary events, such as inflammation-induced signaling via the epidermal growth factor receptor (EGFR) and expression of the SOX9 gene, are required for tumor formation. Herein we sought to identify the mechanisms that link EGFR signaling with activation of SOX9 during acinar-ductal metaplasia, a transdifferentiation process that precedes pancreatic carcinogenesis. METHODS: We analyzed pancreatic tissues from KrasG12D; pdx1-Cre and KrasG12D; NFATc1D/D; pdx1-Cre mice after intraperitoneal administration of caerulein, vs cyclosporin A or dimethyl sulfoxide (controls). Induction of EGFR signaling and its effects on the expression of Nuclear factor of activated T cells c1 (NFATc1) or SOX9 were investigated by quantitative reverse-transcription polymerase chain reaction, immunoblot, and immunohistochemical analyses of mouse and human tissues and acinar cell explants. Interactions between NFATc1 and partner proteins and effects on DNA binding or chromatin modifications were studied using co-immunoprecipitation and chromatin immunoprecipitation assays in acinar cell explants and mouse tissue. RESULTS: EGFR activation induced expression of NFATc1 in metaplastic areas from patients with chronic pancreatitis and in pancreatic tissue from KrasG12D mice. EGFR signaling also promoted formation of a complex between NFATc1 and C-JUN in dedifferentiating mouse acinar cells, leading to activation of Sox9 transcription and induction of acinar-ductal metaplasia. Pharmacologic inhibition of NFATc1 or disruption of the Nfatc1 gene inhibited EGFR-mediated induction of Sox9 transcription and blocked acinar-ductal transdifferentiation and pancreatic cancer initiation in mice. CONCLUSIONS: EGFR signaling induces expression of NFATc1 and Sox9, leading to acinar cell transdifferentiation and initiation of pancreatic cancer. Strategies designed to disrupt this pathway might be developed to prevent pancreatic cancer initiation in high-risk patients with chronic pancreatitis.
资助项目	DFGGerman Research Foundation (DFG)European Commission [KFO210, SFB-TR17]; German Cancer Research Foundation [109423, 109992]; Mildred Scheel FellowshipDeutsche Krebshilfe; Mayo Foundation for Medical Research; Center for Regenerative Medicine; Mayo Clinic Jacksonville; National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01 CA140182, RO1 CA172045]; National Cancer Institute Pancreas SPORE [P50 CA102701]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA015083, R01CA140182, P50CA102701, R01CA172045] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [P30DK063720] Funding Source: NIH RePORTER
出版者	W B SAUNDERS CO-ELSEVIER INC
出版地	PHILADELPHIA
ISSN	0016-5085
EISSN	1528-0012
卷号	148 期号:5 页码:1024-U502
DOI	10.1053/j.gastro.2015.01.033
页数	20
WOS类目	Gastroenterology & Hepatology
WOS研究方向	Gastroenterology & Hepatology
WOS记录号	WOS:000353335700033
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	25623042
PMC记录号	PMC4409493
SCOPUSEID	2-s2.0-84928604113
通讯作者地址	[Hessmann, Elisabeth]Gastroenterology and Gastrointestinal Oncology,University Medical Center Goettingen,Robert Koch Strasse 40,Goettingen,37075,Germany
Scopus学科分类	Hepatology;Gastroenterology
引用统计	被引频次：53[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/20239
专题	药学院（分析测试中心）药学院（分析测试中心）_生物制药系_生物制药工程
通讯作者	Hessmann, Elisabeth
作者单位	1.Gastroenterology and Gastrointestinal Oncology,University Medical Center Goettingen,Robert Koch Strasse 40,Goettingen,37075,Germany; 2.Clinic for General,Visceral and Pediatric Surgery,University Medical Center Goettingen,Goettingen,Germany; 3.Signaling and Transcription Laboratory,Department of Gastroenterology,Philipps-University,Marburg,Germany; 4.Schulze Center for Novel Therapeutics,Division of Oncology Research,Mayo Clinic,Rochester,United States; 5.Department of Cancer Biology,Mayo Clinic,Jacksonville,United States; 6.School of Pharmaceutical Sciences,Key Laboratory of Biotechnology and Pharmaceutical Engineering,Wenzhou Medical University,Wenzhou, Zhejiang,China; 7.Diabetes Center,University of California San Francisco,San Francisco,United States; 8.II Medizinische Klinik,Klinikum Rechts der Isar,Technische Universität,Munich,Germany
推荐引用方式 GB/T 7714	Chen, Nai-Ming,Singh, Garima,Koenig, Alexander,et al. NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas[J]. GASTROENTEROLOGY,2015,148(5):1024-U502.
APA	Chen, Nai-Ming., Singh, Garima., Koenig, Alexander., Liou, Geou-Yarh., Storz, Peter., ... & Hessmann, Elisabeth. (2015). NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas. GASTROENTEROLOGY, 148(5), 1024-U502.
MLA	Chen, Nai-Ming,et al."NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas".GASTROENTEROLOGY 148.5(2015):1024-U502.