Abstract
s / Pancreatology 12 (2012) 502–597 549 Introduction: Inflammation along with activating mutations of the oncogene Kras is a central risk factor for pancreatic cancer development. Signaling induced by inflammatory processes involves nuclear factor of activated T cells (NFAT) pathways. NFATc1 is overexpressed and activated in Kras-mutated human pancreatic cancers where it mediates cancer growth stimulation. Aim: This study aims to determine the in vivo role of NFATc1 in Krasdependent carcinogenesis. Methods: Transgenic mice conditionally expressing mutated KrasG12D and/or nuclear NFATc1 (NKC mice) and NFATc1 knockout mice were engineered and analyzed in terms of (inflammation-induced) carcinogenesis. Immunohistochemistry, Western blot and qPCR analyses, ChIPSeq and genome-wide expression profiling were performed to investigate the mechanisms of NFATc1-Kras cooperation in tissues and tumor cells isolated from NKC tumors. Results: Concomitant activation of NFATc1 and Kras as a result of inflammation or in NKC mice dramatically accelerated carcinogenesis and reduced survival. Mechanistically, nuclear NFATc1 activated expression of oncogenic STAT3 transcription factors. High correlative expression levels of NFATc1 and p-STAT3 could be confirmed by immunohistological and immunofluorescence staining of human and murine cancer tissues. ActivatedSTAT3 in turnphysically interactedwithNFATc1 to regulate its binding to chromatin enhancer sites and subsequently stimulated NFATc1-dependent gene transcription of newly-identified target genes during pancreatic carcinogenesis. Pharmacologic and genetic depletion of the NFATc1/STAT3axis significantly arrested carcinogenesis in mouse models and confirmed the requirement of NFATc1 in Kras-driven pancreatic carcinogenesis. Conclusion: We identified a previously unknown oncogenic cooperation between NFATc1 and Kras which governs pancreatic cancer progression and opens new insights into future therapeutic approaches.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
