Overexpression of hedgehog signaling molecules and its involvement in the proliferation of endometrial carcinoma cells
Overexpression of hedgehog signaling molecules and its involvement in the proliferation of endometrial carcinoma cells
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DOI：
10.1158/1078-0432.ccr-06-1407
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发表时间：
2007-03-01
影响因子：
11.5
通讯作者：
Konishi, Ikuo
中科院分区：
文献类型：
--
作者：
Feng, Yu-Zhen;Shiozawa, Tanri;Konishi, Ikuo
目的：研究发现Hedgehog通路在人类恶性肿瘤中异常激活。本研究旨在研究Hedgehog通路在子宫内膜组织中的表达及其功能参与。实验设计：检测Sonic Hedgehog(Shh)、Patched(Ptch)、Smoothened(Smo)和Gli1在不同子宫内膜组织和子宫内膜癌细胞系中的表达。结果：Shh、Ptch、Smo和Gli1在正常子宫内膜中的表达很弱，在子宫内膜增生症和子宫内膜癌中的表达逐渐增强，差异有统计学意义。这些分子在不同分期、不同组织学分级的癌组织中的表达无明显差异。与对照组相比，Hedgehog途径的特异性抑制剂环丙胺对子宫内膜癌Ishikawa和HHUA细胞的生长抑制分别为56%和67%。向HHUA细胞中加入重组Shh肽后，HHUA细胞的增殖率提高了41%。用小干扰RNA(SiGli1)沉默Gli1导致细胞生长抑制和PTCH表达下调。此外，环多巴胺/siGli1诱导的生长抑制与细胞周期蛋白D1、A和N-myc的下调有关。结论：该通路的异常激活可能以自分泌/旁分泌的方式参与子宫内膜癌细胞的增殖，提示Hedgehog通路有可能成为一种新的分子靶向途径。
Purpose: Research has revealed abnormal activation of the hedgehog pathway in human malignancies. The present study was undertaken to examine the expression and functional involvement of the hedgehog pathway in endometrial tissues.Experimental Design: The expression of sonic hedgehog (Shh), patched (Ptch), Smoothened (Smo), and Gli1 was examined in various endometrial tissues and endometrial carcinoma cell lines. The effect of hedgehog signaling on the proliferation of endometrial carcinoma cell lines was also examined.Results: The expression of Shh, Ptch, Smo, and Gli1 was very weak in normal endometrium, but was increased in endometrial hyperplasia and carcinoma stepwisely with significant differences. There was no marked difference in the expression of these molecules in carcinomas according to stages and histologic grades. Treatment with cyclopamine, a specific inhibitor of the hedgehog pathway, for endometrial carcinoma Ishikawa and HHUA cells suppressed growth by 56% and 67%, respectively, compared with the control. The addition of recombinant Shh peptide to HHUA cells enhanced their proliferation by 41%. The silencing of Gli1 using small interfering RNA (siGli1) resulted in the growth suppression and down-regulation of Ptch expression. In addition, the cyclopamine/siGli1-induced growth suppression was associated with the down-regulation of cyclins D1 and A and N-myc. No somatic mutations for ptch and smo genes were detected in the endometrial carcinoma cases examined.Conclusions: The abnormal activation of this pathway is involved in the proliferation of endometrial carcinoma cells possibly in an auto-/paracrine fashion, suggesting the possibility of the hedgehog pathway being a novel candidate for molecular targeting.