Feng Yu-Zhen, Shiozawa Tanri, Miyamoto Tsutomu, Kashima Hiroyasu, Kurai Miyuki, Suzuki Akihisa, Ying-Song Jiang, Konishi Ikuo
Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Asahi, Matsumoto, Japan.
Clin Cancer Res. 2007 Mar 1;13(5):1389-98. doi: 10.1158/1078-0432.CCR-06-1407.
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.
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.
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.
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.
研究表明刺猬信号通路在人类恶性肿瘤中存在异常激活。本研究旨在检测刺猬信号通路在子宫内膜组织中的表达及功能参与情况。
检测了多种子宫内膜组织及子宫内膜癌细胞系中声波刺猬因子（Shh）、patched（Ptch）、Smoothened（Smo）和Gli1的表达。还检测了刺猬信号对子宫内膜癌细胞系增殖的影响。
Shh、Ptch、Smo和Gli1在正常子宫内膜中的表达非常弱，但在子宫内膜增生和癌组织中呈逐步增加，差异有统计学意义。这些分子在不同分期和组织学分级的癌组织中的表达无明显差异。用刺猬信号通路特异性抑制剂环杷明处理子宫内膜癌Ishikawa和HHUA细胞，与对照组相比，细胞生长分别抑制了56%和67%。向HHUA细胞中添加重组Shh肽可使其增殖增强41%。用小干扰RNA（siGli1）沉默Gli1导致细胞生长抑制及Ptch表达下调。此外，环杷明/siGli1诱导的生长抑制与细胞周期蛋白D1、A及N-myc的下调有关。在所检测的子宫内膜癌病例中未检测到ptch和smo基因的体细胞突变。
该通路的异常激活可能以自分泌/旁分泌方式参与子宫内膜癌细胞的增殖，提示刺猬信号通路可能是分子靶向治疗的新候选靶点。
