TY - JOUR
T1 - The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis
AU - Reichert, Maximilian
AU - Takano, Shigetsugu
AU - Von Burstin, Johannes
AU - Kim, Sang Bae
AU - Lee, Ju Seog
AU - Ihida-Stansbury, Kaori
AU - Hahn, Christopher
AU - Heeg, Steffen
AU - Schneider, Gunter
AU - Rhim, Andrew D.
AU - Stanger, Ben Z.
AU - Rustgi, Anil K.
PY - 2013/2/1
Y1 - 2013/2/1
N2 - Pancreatic exocrine cell plasticity can be observed during development, pancreatitis with subsequent regeneration, and also transformation. For example, acinar-ductal metaplasia (ADM) occurs during acute pancreatitis and might be viewed as a prelude to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) development. To elucidate regulatory processes that overlap ductal development, ADM, and the progression of normal cells to PanIN lesions, we undertook a systematic approach to identify the Prrx1 paired homeodomain Prrx1 transcriptional factor as a highly regulated gene in these processes. Prrx1 annotates a subset of pancreatic ductal epithelial cells in Prrx1creERT2-IRES-GFP mice. Furthermore, sorted Prrx1+ cells have the capacity to self-renew and expand during chronic pancreatitis. The two isoforms, Prrx1a and Prrx1b, regulate migration and invasion, respectively, in pancreatic cancer cells. In addition, Prrx1b is enriched in circulating pancreatic cells (Pdx1cre;LSL-KrasG12D/+;p53fl/+;R26YFP). Intriguingly, the Prrx1b isoform, which is also induced in ADM, binds the Sox9 promoter and positively regulates Sox9 expression. This suggests a new hierarchical scheme whereby a Prrx1-Sox9 axis may influence the emergence of acinar-ductal metaplasia and regeneration. Furthermore, our data provide a possible explanation of why pancreatic cancer is skewed toward a ductal fate.
AB - Pancreatic exocrine cell plasticity can be observed during development, pancreatitis with subsequent regeneration, and also transformation. For example, acinar-ductal metaplasia (ADM) occurs during acute pancreatitis and might be viewed as a prelude to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) development. To elucidate regulatory processes that overlap ductal development, ADM, and the progression of normal cells to PanIN lesions, we undertook a systematic approach to identify the Prrx1 paired homeodomain Prrx1 transcriptional factor as a highly regulated gene in these processes. Prrx1 annotates a subset of pancreatic ductal epithelial cells in Prrx1creERT2-IRES-GFP mice. Furthermore, sorted Prrx1+ cells have the capacity to self-renew and expand during chronic pancreatitis. The two isoforms, Prrx1a and Prrx1b, regulate migration and invasion, respectively, in pancreatic cancer cells. In addition, Prrx1b is enriched in circulating pancreatic cells (Pdx1cre;LSL-KrasG12D/+;p53fl/+;R26YFP). Intriguingly, the Prrx1b isoform, which is also induced in ADM, binds the Sox9 promoter and positively regulates Sox9 expression. This suggests a new hierarchical scheme whereby a Prrx1-Sox9 axis may influence the emergence of acinar-ductal metaplasia and regeneration. Furthermore, our data provide a possible explanation of why pancreatic cancer is skewed toward a ductal fate.
KW - Acinar-ductal metaplasia
KW - Pancreatic ductal epithelial cell
KW - Pancreatitis
KW - Prrx1
KW - Sox9
UR - http://www.scopus.com/inward/record.url?scp=84873488509&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873488509&partnerID=8YFLogxK
U2 - 10.1101/gad.204453.112
DO - 10.1101/gad.204453.112
M3 - Article
C2 - 23355395
AN - SCOPUS:84873488509
SN - 0890-9369
VL - 27
SP - 288
EP - 300
JO - Genes and Development
JF - Genes and Development
IS - 3
ER -