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慢性胰腺炎扩张导管中Notch信号通路激活的证据。

Evidence of Notch pathway activation in the ectatic ducts of chronic pancreatitis.

作者信息

Bhanot Uk, Köhntop R, Hasel C, Möller P

机构信息

Department of Pathology, University of Ulm, Ulm, Germany.

出版信息

J Pathol. 2008 Feb;214(3):312-9. doi: 10.1002/path.2293.

Abstract

Ductal concretions in chronic pancreatitis (CP) are one of the causes of ductal obstruction, resulting in pancreatic ductal hypertension (PDH) and duct ectasia. Ductal epithelium subjected to chronic stress by PDH may undergo molecular alterations, thereby not only initiating and sustaining the inflammatory process but also activating molecules that have transforming potential. Acino-ductal metaplasia and pancreatic intraepithelial neoplasia (PanIN) are frequently seen in CP. Using laser capture microdissection, cDNA microarrays and Ingenuity Pathways Analysis, we found an altered Notch pathway in the ectatic ducts of CP. The microarray data was further validated by real-time PCR. We also found elevated transcripts of Notch receptors, Notch1 and Notch3 in microdissected ectatic ducts of CP. The Notch pathway ligands, Jagged/Delta-like and a Notch target, HES-related repressor protein (HERP), were up-regulated in ectatic compared to normal pancreatic ducts, while another target of Notch, hairy/enhancer of split (HES), was down-regulated. The transcripts of Delta-like1 and Jagged1 were increased 3.7-fold and 1.3-fold, respectively, while those of HERP1 were elevated 2.4-fold in the ectatic ducts of CP, compared to normal ducts. Immunohistochemistry showed that Jagged1 was not expressed in normal pancreatic ducts, while it was highly expressed in ectatic ducts. This pattern of Notch component alteration in ectatic ducts was mimicked to some extent in vitro in a human pancreatic duct epithelial (HPDE) cell line, when subjected to a pressure of 200 mmHg for 24 h. Therefore, we conclude that in the ectatic ducts of CP, PDH activates signalling pathways such as Notch, which have transforming potential.

摘要

慢性胰腺炎(CP)中的导管结石是导管阻塞的原因之一,导致胰管高压(PDH)和导管扩张。受到PDH慢性应激的导管上皮可能会发生分子改变,从而不仅启动和维持炎症过程,还会激活具有转化潜能的分子。腺泡-导管化生和胰腺上皮内瘤变(PanIN)在CP中很常见。通过激光捕获显微切割、cDNA微阵列和 Ingenuity 通路分析,我们发现CP扩张导管中的Notch通路发生了改变。微阵列数据通过实时PCR进一步验证。我们还发现CP显微切割的扩张导管中Notch受体Notch1和Notch3的转录本升高。与正常胰管相比,Notch通路配体Jagged/Delta样和一个Notch靶点HES相关阻遏蛋白(HERP)在扩张导管中上调,而Notch的另一个靶点毛状/分裂增强子(HES)下调。与正常导管相比,CP扩张导管中Delta样1和Jagged1的转录本分别增加了3.7倍和1.3倍,而HERP1的转录本升高了2.4倍。免疫组织化学显示,Jagged1在正常胰管中不表达,而在扩张导管中高度表达。当在体外对人胰管上皮(HPDE)细胞系施加200 mmHg的压力24小时时,扩张导管中Notch成分的这种改变模式在一定程度上得到了模拟。因此,我们得出结论,在CP的扩张导管中,PDH激活了具有转化潜能的信号通路,如Notch。

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