Indian hedgehog signaling pathway:: Expression and regulation in pancreatic cancer
Indian hedgehog signaling pathway:: Expression and regulation in pancreatic cancer
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DOI：
10.1002/ijc.20194
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发表时间：
2004-07-10
影响因子：
6.4
通讯作者：
Friess, H
中科院分区：
文献类型：
--
作者：
Kayed, H;Kleeff, J;Friess, H
胰腺癌是一种侵袭性恶性肿瘤，表现出许多遗传和表观遗传改变。Indian hedgehog（Ihh）及其2种信号受体patched（Ptc）和smoothened（Smo）参与胰腺发育和β细胞功能调节以及某些人类肿瘤。本研究分析了Ihh及其受体在胰腺癌中的表达、分布和功能。采用定量RT-PCR和免疫组织化学方法分析lhh、Ptc和Smo的表达、定位和转录调控。通过MTT细胞生长测定法检测抑制和刺激hedgehog信号通路对胰腺癌细胞生长的影响。通过定量RT-PCR，lhh，Ptc和Smo mRNA水平分别增加35-，1.2-和1.6-倍，在胰腺癌组织相比，正常胰腺组织。免疫组化结果显示lhh、Ptc和Smo在正常组织、胰腺癌组织和胰腺癌细胞中均有表达。Hedgehog受体拮抗剂环巴胺通过G（0）/G（1）阻滞对胰腺癌细胞的生长产生密切依赖性抑制。相反，lhh激动剂对胰腺癌细胞生长没有显著影响。TGF-β I抑制了TGF-β I反应性胰腺癌细胞系中的Ihh转录，但对其他测试细胞系没有影响。总之，lhh及其受体Ptc和Smo在胰腺癌中表达，并且hedgehog信号传导的阻断导致胰腺癌细胞生长的抑制，这表明Ihh信号传导途径的异常激活有助于这种恶性肿瘤的肿瘤发展。(C)2004 Wiley-Liss，Inc.
Pancreatic cancer is an aggressive malignancy that exhibits a number of genetic and epigenetic alterations. Indian hedgehog (Ihh) and its 2 signaling receptors, patched (Ptc) and smoothened (Smo), are involved in pancreatic development and regulation of beta-cell function as well as in certain human tumors. In the current study, we analyzed the expression, distribution and function of Ihh and its receptors in pancreatic cancer. Quantitative RT-PCR and immunohistochemistry were utilized to analyze the expression, localization and transcriptional regulation of lhh, Ptc and Smo. The effects of inhibition and stimulation of the hedgehog signaling pathway on pancreatic cancer cell growth were examined by the MTT cell growth assay. By quantitative RT-PCR, lhh, Ptc and Smo mRNA levels were increased 35-, 1.2- and 1.6-fold, respectively, in pancreatic cancer tissues in comparison to normal pancreatic tissues. By immunohistochemistry, lhh, Ptc and Smo were expressed in the islet cells of normal and cancerous tissues and in pancreatic cancer cells. The growth of pancreatic cancer cells was close-dependently inhibited by the hedgehog antagonist cyclopamine through G(0)/G(1) arrest. In contrast, lhh agonists exhibited no significant effect on pancreatic cancer cell growth. TGF-betaI repressed Ihh transcription in a TGF-betaI-responsive pancreatic cancer cell line, but had no effect on the other tested cell lines. In conclusion, lhh and its receptors Ptc and Smo are expressed in pancreatic cancer, and blockage of hedgehog signaling results in inhibition of pancreatic cancer cell growth, suggesting that aberrant activation of the Ihh signaling pathway contributes to tumor development in this malignancy. (C) 2004 Wiley-Liss, Inc.