Abstract
Pancreatic differentiation 2 (PD2), a PAF (RNA Polymerase II Associated Factor) complex subunit, is overexpressed in pancreatic cancer cells and has demonstrated potential oncogenic property. Here, we report that PD2/Paf1 expression was restricted to acinar cells in the normal murine pancreas, but its expression increased in the ductal cells of KrasG12D/Pdx1Cre (KC) mouse model of pancreatic cancer with increasing age, showing highest expression in neoplastic ductal cells of 50 weeks old mice. PD2/Paf1 was specifically expressed in amylase and CK19 double positive metaplastic ducts, representing intermediate structures during pancreatic acinar-to-ductal metaplasia (ADM). Similar PD2/Paf1 expression was observed in murine pancreas that exhibited ADM-like histology upon cerulein challenge. In normal mice, cerulein-mediated inflammation induced a decrease in PD2/Paf1 expression, which was later restored upon recovery of the pancreatic parenchyma. In KC mice, however, PD2/Paf1 mRNA level continued to decrease with progressive dysplasia and subsequent neoplastic transformation. Additionally, knockdown of PD2/Paf1 in pancreatic acinar cells resulted in the abrogation of Amylase, Elastase and Lipase (acinar marker) mRNA levels with simultaneous increase in CK19 and CAII (ductal marker) transcripts. In conclusion, our studies indicate loss of PD2/Paf1 expression during acinar transdifferentiation in pancreatic cancer initiation and PD2/Paf1 mediated regulation of lineage specific markers.
Highlights
Pancreatic cancer (PC) is a lethal desmoplastic tumor with a 5-year survival rate of less than 6% [1]
Since Pancreatic differentiation 2 (PD2)/Paf1 was differentially expressed in human pancreatic cancer cells, we explored its expression in the floxed KrasG12D animals along with their contemporary normal littermates harboring either LSLKrasG12D or Pdx1-Cre at different time points during pancreatic cancer progression (N=8 for each time point)
We analyzed by quantitative real time Polymerase chain reaction (PCR), the mRNA expression of PD2/Paf1 in mice at different ages
Summary
Pancreatic cancer (PC) is a lethal desmoplastic tumor with a 5-year survival rate of less than 6% [1]. Current tenet suggests ‘acinar-to-ductal metaplasia’ as the initiating event of pancreatic ductal adenocarcinoma This phenomenon defined as the transformation of one differentiated cell type into another is characterized by loss of acinar cell polarity and gene signatures and gradual conversion of acinar structures into duct-like phenotype. During this process transitional metaplastic cells are formed, some of which produce the precursor PanIN lesions that predispose the pancreatic parenchyma to neoplastic transformation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
