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Baumgart, S.* ; Chen, N.* ; Siveke, J.T.* ; König, A.O.* ; Zhang, J.* ; Singh, S.K.* ; Wolf, E.* ; Bartkuhn, M.* ; Esposito, I. ; Heßmann, E.* ; Reinecke, J.* ; Nikorowitsch, J.* ; Brunner, M.* ; Singh, G.P.* ; Fernández-Zapico, M.E.* ; Smyrk, T.C.* ; Bamlet, W.R.* ; Eilers, M.* ; Neeße, A.* ; Gress, T.M.* ; Billadeau, D.D.* ; Tuveson, D.A.* ; Urrutia, R.A.* ; Ellenrieder, V.*

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

Cancer Discov. 4, 688-701 (2014)
DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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 KrasG12D 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 signifi cant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
ISSN (print) / ISBN 2159-8274
e-ISSN 2159-8290
Zeitschrift Cancer Discovery
Quellenangaben Band: 4, Heft: 6, Seiten: 688-701 Artikelnummer: , Supplement: ,
Verlag American Association for Cancer Research (AACR)
Verlagsort Philadelphia, Pa.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pathology (PATH)