title: Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia.
abstract: OBJECTIVE
  Growing evidence suggests that a phenotypic switch converting pancreatic acinar cells to duct-like cells can lead to pancreatic intraepithelial neoplasia and eventually to invasive pancreatic ductal adenocarcinoma. Histologically, the onset of this switch is characterised by the co-expression of acinar and ductal markers in acini, a lesion called acinar-to-ductal metaplasia (ADM). The transcriptional regulators required to initiate ADM are unknown, but need to be identified to characterise the regulatory networks that drive ADM. In this study, the role of the ductal transcription factors hepatocyte nuclear factor 6 (HNF6, also known as Onecut1) and SRY-related HMG box factor 9 (Sox9) in ADM was investigated.
  
  
  METHODS
  Expression of HNF6 and Sox9 was measured by immunostaining in normal and diseased human pancreas. The function of the factors was tested in cultured cells and in mouse models of ADM by a combination of gain and loss of function experiments.
  
  
  RESULTS
  Expression of HNF6 and Sox9 was ectopically induced in acinar cells in human ADM as well as in mouse models of ADM. HNF6 and, to a lesser extent, Sox9 were required for repression of acinar genes, for modulation of ADM-associated changes in cell polarity and for activation of ductal genes in metaplastic acinar cells.
  
  
  CONCLUSIONS
  HNF6 and Sox9 are new biomarkers of ADM and constitute candidate targets for preventive treatment in cases when ADM may lead to cancer. This work also shows that ectopic activation of transcription factors may underlie metaplastic processes occurring in other organs.
authors.affiliation: Université catholique de Louvain, de Duve Institute, Avenue Hippocrate 75/B1-7503, B-1200 Brussels, Belgium.
authors.forename: Pierre-Paul
authors.initials: PP
authors.lastname: Prévot
authors.forename: Alexandru
authors.initials: A
authors.lastname: Simion
authors.forename: Adrien
authors.initials: A
authors.lastname: Grimont
authors.forename: Marta
authors.initials: M
authors.lastname: Colletti
authors.forename: Abed
authors.initials: A
authors.lastname: Khalaileh
authors.forename: Géraldine
authors.initials: G
authors.lastname: Van den Steen
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Xu
authors.forename: Véronique
authors.initials: V
authors.lastname: Roelants
authors.forename: Jacob
authors.initials: J
authors.lastname: Hald
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Konieczny
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
authors.forename: Frédéric P
authors.initials: FP
authors.lastname: Lemaigre
authors.forename: Patrick
authors.initials: P
authors.lastname: Jacquemin
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D006168:Guinea Pigs; D051559:Hepatocyte Nuclear Factor 6 / Q000378:metabolism*; D006801:Humans; D008679:Metaplasia; D051379:Mice; D023421:Models, Animal; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D051559:Hepatocyte Nuclear Factor 6; C496606:Onecut1 protein, mouse; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse