1. Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D.
- Author
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Baumgart S, Chen NM, Siveke JT, König A, Zhang JS, Singh SK, Wolf E, Bartkuhn M, Esposito I, Heßmann E, Reinecke J, Nikorowitsch J, Brunner M, Singh G, Fernandez-Zapico ME, Smyrk T, Bamlet WR, Eilers M, Neesse A, Gress TM, Billadeau DD, Tuveson D, Urrutia R, and Ellenrieder V
- Subjects
- Animals, Cell Line, Tumor, Ceruletide, Gene Expression Regulation, Neoplastic, Mice, Transgenic, NFATC Transcription Factors genetics, Pancreatic Neoplasms genetics, Pancreatitis chemically induced, Pancreatitis genetics, Proto-Oncogene Proteins p21(ras) genetics, STAT3 Transcription Factor genetics, NFATC Transcription Factors metabolism, Pancreatic Neoplasms metabolism, Pancreatitis metabolism, Proto-Oncogene Proteins p21(ras) metabolism, STAT3 Transcription Factor metabolism
- Abstract
Unlabelled: Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote Kras(G12D)-driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in Kras(G12D) mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer-promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1-STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials., Significance: Our study points to the existence of an oncogenic NFATc1-STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1-STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has significant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies., (©2014 American Association for Cancer Research.)
- Published
- 2014
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