Dey Parama, Rachagani Satyanarayana, Vaz Arokia P, Ponnusamy Moorthy P, Batra Surinder K
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, U.S.A.
Oncotarget. 2014 Jun 30;5(12):4480-91. doi: 10.18632/oncotarget.2041.
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.
胰腺分化2（PD2）是一种PAF（RNA聚合酶II相关因子）复合体亚基，在胰腺癌细胞中过表达，并已显示出潜在的致癌特性。在此，我们报告PD2/Paf1的表达在正常小鼠胰腺中局限于腺泡细胞，但在胰腺癌的KrasG12D/Pdx1Cre（KC）小鼠模型的导管细胞中，其表达随年龄增长而增加，在50周龄小鼠的肿瘤性导管细胞中表达最高。PD2/Paf1在淀粉酶和细胞角蛋白19双阳性化生导管中特异性表达，代表胰腺腺泡-导管化生（ADM）过程中的中间结构。在经雨蛙肽刺激后呈现ADM样组织学的小鼠胰腺中观察到类似的PD2/Paf1表达。在正常小鼠中，雨蛙肽介导的炎症导致PD2/Paf1表达下降，在胰腺实质恢复后其表达随后恢复。然而，在KC小鼠中，随着发育异常的进展和随后的肿瘤转化，PD2/Paf1 mRNA水平持续下降。此外，在胰腺腺泡细胞中敲低PD2/Paf1导致淀粉酶、弹性蛋白酶和脂肪酶（腺泡标志物）mRNA水平消失，同时细胞角蛋白19和CAII（导管标志物）转录本增加。总之，我们的研究表明在胰腺癌起始过程中腺泡转分化期间PD2/Paf1表达缺失以及PD2/Paf1介导的谱系特异性标志物调控。
