NFATc4 Regulates Sox9 gene expression in acinar cell plasticity and pancreatic cancer initiation

Elisabeth Hessmann, Jin San Zhang, Nai Ming Chen, Marie Hasselluhn, Geou Yarh Liou, Peter Storz, Volker Ellenrieder, Daniel D. Billadeau, Alexander Koenig

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number5272498
JournalStem Cells International
Volume2016
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Hessmann, E., Zhang, J. S., Chen, N. M., Hasselluhn, M., Liou, G. Y., Storz, P., Ellenrieder, V., Billadeau, D. D., & Koenig, A. (2016). NFATc4 Regulates Sox9 gene expression in acinar cell plasticity and pancreatic cancer initiation. Stem Cells International, 2016, [5272498]. https://doi.org/10.1155/2016/5272498