The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis.
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 Prrx1creER(T2)-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-Kras(G12D/+);p53(fl/+);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.
Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Maximilian
M
Reichert
Shigetsugu
S
Takano
Johannes
J
von Burstin
Sang-Bae
SB
Kim
Ju-Seog
JS
Lee
Kaori
K
Ihida-Stansbury
Christopher
C
Hahn
Steffen
S
Heeg
Günter
G
Schneider
Andrew D
AD
Rhim
Ben Z
BZ
Stanger
Anil K
AK
Rustgi
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000166:cytology / Q000473:pathology* / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000503:physiopathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D055758:SOX9 Transcription Factor / Q000235:genetics
D018398:Homeodomain Proteins; D020033:Protein Isoforms; C489936:Prrx1 protein, mouse; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse