Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of hedgehog signaling on pancreatic ductal epithelial cells
Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of hedgehog signaling on pancreatic ductal epithelial cells
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DOI：
10.1158/0008-5472.can-04-1413
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发表时间：
2005-03-01
期刊：
影响因子：
11.2
通讯作者：
Leach, SD
中科院分区：
文献类型：
--
作者：
Prasad, NB;Biankin, AV;Leach, SD
侵袭性胰腺癌被认为是通过一系列称为胰腺上皮内瘤变(Panin)的非侵袭性导管病变发展而来的。我们使用cDNA微阵列询问了15,000个转录本，以确定在显微切割的早期PAIN病变(Panin-1B/2)中与显微切割的正常导管上皮相比差异表达的49个基因。在这项分析中，一组胰外前庭标志物，包括胃蛋白酶原C，MUC6，KLF4和TFF1，在Panin中被发现上调。使用实时逆转录-聚合酶链式反应、原位杂交和免疫组织化学相结合的方法，进一步验证了81名患者的150个早期PAIN皮损中这些基因的上调。对人Panin中这些胃肠道转录物的鉴定促使通过半定量和实时逆转录-聚合酶链式反应对其他前肠标志物进行评估，揭示了SOX-2、胃泌素、HoxA5、GATA4/5/6、Villin和Forkbead 6(FoxI1)的上调。与多种胃上皮标志物的频繁表达不同，肠道标志物肠脂肪酸结合蛋白CDX1和CDX2在胰腺癌和胰腺癌皮损中很少表达。将Gli1基因导入永生化的人胰腺导管上皮细胞，可诱导Hedgehog通路激活，导致早期PanIN病变中的大部分前肠标志物表达上调。这些数据显示早期Panin病变中前肠标志物的频繁上调，并提示Panin的发育可能涉及Hedgehog介导的向胃上皮分化程序的转化。
Invasive pancreatic cancer is thought to develop through a series of noninvasive duct lesions known as pancreatic intraepithelial neoplasia (PanIN). We used cDNA microarrays interrogating 15,000 transcripts to identify 49 genes that were differentially expressed in microdissected early PanIN lesions (PanIN-1B/2) compared with microdissected normal duct epithelium. In this analysis, a cluster of extrapancreatic foregut markers, including pepsinogen C, MUC6, KLF4, and TFF1, was found to be up-regulated in PanIN. Up-regulation of these genes was further validated using combinations of real-time reverse transcription-PCR, in situ hybridization, and immunohistochemistry in a total of 150 early PanIN lesions from 81 patients. Identification of these gastrointestinal transcripts in human PanIN prompted assessment of other foregut markers by both semiquantitative and realtime reverse transcription-PCR, revealing similar upregulation of Sox-2, Gastrin, HoxA5, GATA4/5/6, Villin and Forkbead 6 (FoxI1). In contrast to frequent expression of multiple gastric epithelial markers, the intestinal markers intestinal fatty acid binding protein, CDX1 and CDX2 were rarely expressed either in PanIN lesions or in invasive pancreatic cancer. Hedgehog pathway activation induced by transfection of immortalized human pancreatic ductal epithelial cells with Gli1 resulted in up-regulation of the majority of foregut markers seen in early PanIN lesions. These data show frequent up-regulation of foregut markers in early PanIN lesions and suggest that PanIN development may involve Hedgehog-mediated conversion to a gastric epithelial differentiation program.