TY - JOUR
T1 - Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia
AU - Prévot, Pierre Paul
AU - Simion, Alexandru
AU - Grimont, Adrien
AU - Colletti, Marta
AU - Khalaileh, Abed
AU - Van Den Steen, Geráldine
AU - Sempoux, Christine
AU - Xu, Xiaobo
AU - Roelants, Véronique
AU - Hald, Jacob
AU - Bertrand, Luc
AU - Heimberg, Harry
AU - Konieczny, Stephen F.
AU - Dor, Yuval
AU - Lemaigre, Frédéric P.
AU - Jacquemin, Patrick
PY - 2012/12
Y1 - 2012/12
N2 - 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. Design: 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.
AB - 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. Design: 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.
UR - http://www.scopus.com/inward/record.url?scp=84868698484&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2011-300266
DO - 10.1136/gutjnl-2011-300266
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C2 - 22271799
AN - SCOPUS:84868698484
SN - 0017-5749
VL - 61
SP - 1723
EP - 1732
JO - Gut
JF - Gut
IS - 12
ER -
