PD2/Paf1 depletion in pancreatic acinar cells promotes acinar-to-ductal metaplasia.
PD2/Paf1 depletion in pancreatic acinar cells promotes acinar-to-ductal metaplasia.
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DOI：
10.18632/oncotarget.2041
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发表时间：
2014-06-30
期刊：
影响因子：
--
通讯作者：
Batra SK
中科院分区：
文献类型：
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作者：
Dey P;Rachagani S;Vaz AP;Ponnusamy MP;Batra SK
胰腺分化2(PD2)是一种PAF(RNA聚合酶II相关因子)复合亚单位，在胰腺癌细胞中高表达，具有潜在的致癌作用。在此，我们报道了PD2/Paf1在正常小鼠胰腺的腺泡细胞中的表达，但在Pdx1Cre；KrasG12D(KC)小鼠胰腺癌模型中随着年龄的增长，其在导管细胞中的表达增加，在50周龄的小鼠肿瘤导管细胞中表达最高。PD2/Paf1在淀粉酶和CK19双阳性化生导管中特异表达，代表胰腺腺泡-导管化生(ADM)过程中的中间结构。PD2/Paf1在蓝蛋白攻击后表现出ADM样组织结构的小鼠胰腺中也有类似的表达。在正常小鼠中，雨蛙素介导的炎症诱导了PD2/Paf1表达的减少，这种表达在胰腺实质恢复后恢复。然而，在KC小鼠中，随着进行性异型增生和随后的肿瘤转化，PD2/Paf1的mRNA水平继续下降。此外，胰腺腺泡细胞中PD2/Paf1基因的敲除导致淀粉酶、弹力酶和脂肪酶(腺泡标志物)的mRNA水平降低，而CK19和CAII(导管标志物)的转录水平同时增加。综上所述，我们的研究表明，在胰腺癌起始的腺泡转分化过程中，PD2/Paf1的表达缺失，并且PD2/Paf1介导了谱系特异性标记的调节。
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.