PD2/Paf1 depletion in pancreatic acinar cells promotes acinar-to-ductal metaplasia
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Parama Dey1, Satyanarayana Rachagani1, Arokia P. Vaz1, Moorthy P. Ponnusamy1 and Surinder K. Batra1,2,3
1 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, U.S.A
2 Fred & Pamela Buffet Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, U.S.A
3 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, U.S.A
Moorthy P. Ponnusamy, email:
Surinder K. Batra, email:
Keywords: ADM, cerulein, pancreatic cancer, PD2/Paf1
Received: April 20, 2014 Accepted: May 28, 2014 Published: May 30, 2014
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 Pdx1Cre; KrasG12D (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.
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