| First Author | Baumgart S | Year | 2014 |
| Journal | Cancer Discov | Volume | 4 |
| Issue | 6 | Pages | 688-701 |
| PubMed ID | 24694735 | Mgi Jnum | J:213422 |
| Mgi Id | MGI:5584334 | Doi | 10.1158/2159-8290.CD-13-0593 |
| Citation | Baumgart S, et al. (2014) Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. Cancer Discov 4(6):688-701 |
| abstractText | 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. |
