Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D.

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.

• Authors: Sandra Baumgart, Nai-Ming Chen, Jens T Siveke, Alexander König, Jin-San Zhang, Shiv K Singh, Elmar Wolf, Marek Bartkuhn, Irene Esposito, Elisabeth Heßmann, Johanna Reinecke, Julius Nikorowitsch, Marius Brunner, Garima Singh, Martin E Fernandez-Zapico, Thomas Smyrk, William R Bamlet, Martin Eilers, Albrecht Neesse, Thomas M Gress, Daniel D Billadeau, David Tuveson, Raul Urrutia, Volker Ellenrieder
• Journal: Cancer discovery (Cancer Discov) Vol. 4 Issue 6 Pg. 688-701 (Jun 2014) ISSN: 2159-8290 [Electronic] United States
• PMID: 24694735 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• NFATC Transcription Factors
• Nfatc1 protein, mouse
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Ceruletide
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Cell Line, Tumor
• Ceruletide
• Gene Expression Regulation, Neoplastic
• Mice, Transgenic
• NFATC Transcription Factors (genetics, metabolism)
• Pancreatic Neoplasms (genetics, metabolism)
• Pancreatitis (chemically induced, genetics, metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• STAT3 Transcription Factor (genetics, metabolism)