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首页> 美国卫生研究院文献>Cancers >The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity Induces E-Cadherin Expression and Reduces Invasion in Colorectal Cancer Cells
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The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity Induces E-Cadherin Expression and Reduces Invasion in Colorectal Cancer Cells

机译：刺猬抑制剂环巴胺可降低大肠癌细胞中β-Catenin-Tcf的转录活性诱导E-Cadherin的表达并减少其侵袭

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Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH) signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist) associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer.
机译：大肠癌是全球性的主要健康问题，每年导致全世界600,000多例死亡，其中大多数是由于转移性疾病引起的。 Wnt信号，特别是与β-catenin相关的转录，已被证明可驱动结直肠瘤形成中的肿瘤发生和转移过程，但其与其他关键信号通路（例如刺猬）的复杂相互作用尚待阐明。先前我们已经表明，刺猬（HH）信号传导途径在结直肠肿瘤细胞中具有活性，并且用环巴胺抑制该途径可诱导细胞凋亡。现在我们显示，环巴胺治疗可减少大肠癌细胞系中β-catenin的相关转录，并且可以通过添加Sonic Hedgehog蛋白来逆转这种作用。我们还显示，环巴胺能同时诱导肿瘤抑制因子和预后指标E-钙粘蛋白的表达。与HH在调节侵袭潜能中的作用一致，我们表明环巴胺降低了与上皮-间充质转化有关的转录因子（Slug，Snail和Twist）的表达，并降低了体外结直肠癌细胞的侵袭性。综上所述，这些数据表明，刺猬通路的药理抑制作用在治疗大肠癌方面具有治疗潜力。

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