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Stem Cells International
Volume 2016 (2016), Article ID 5272498, 11 pages
Research Article

NFATc4 Regulates Sox9 Gene Expression in Acinar Cell Plasticity and Pancreatic Cancer Initiation

1Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Robert-Koch Street 40, 37075 Göttingen, Germany
2Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, 200 1st Street SW No. W4, Rochester, MN 55905, USA
3School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
4Department of Cancer Biology, Mayo Clinic Cancer Center, 4500 San Pablo Road, Jacksonville, FL 32224, USA

Received 15 May 2015; Accepted 12 July 2015

Academic Editor: Silvia Brunelli

Copyright © 2016 Elisabeth Hessmann et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Acinar transdifferentiation toward a duct-like phenotype constitutes the defining response of acinar cells to external stress signals and is considered to be the initial step in pancreatic carcinogenesis. Despite the requirement for oncogenic Kras in pancreatic cancer (PDAC) development, oncogenic Kras is not sufficient to drive pancreatic carcinogenesis beyond the level of premalignancy. Instead, secondary events, such as inflammation-induced signaling activation of the epidermal growth factor (EGFR) or induction of Sox9 expression, are required for tumor formation. Herein, we aimed to dissect the mechanism that links EGFR signaling to Sox9 gene expression during acinar-to-ductal metaplasia in pancreatic tissue adaptation and PDAC initiation. We show that the inflammatory transcription factor NFATc4 is highly induced and localizes in the nucleus in response to inflammation-induced EGFR signaling. Moreover, we demonstrate that NFATc4 drives acinar-to-ductal conversion and PDAC initiation through direct transcriptional induction of Sox9. Therefore, strategies designed to disrupt NFATc4 induction might be beneficial in the prevention or therapy of PDAC.