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首页> 外文期刊>Cell death & disease. >Survivin, a novel target of the Hedgehog/GLI signaling pathway in human tumor cells
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Survivin, a novel target of the Hedgehog/GLI signaling pathway in human tumor cells

机译：Survivin，人类肿瘤细胞中Hedgehog / GLI信号通路的新靶标

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Survivin, an important antiapoptotic protein, is expressed in tumors, whereas in normal tissues the expression of this protein is extremely low, defining a role for survivin as a cancer gene. Survivin exhibits multifunctional activity in tumor cells. However, why survivin expression is sharply and invariably restricted to tumor tissue remains unclear. Here, we identified 11 putative consensus binding sites for GLI transcription factors in the survivin promoter and characterized the promoter activity. Inhibitors of the Hedgehog/GLI pathway, cyclopamine and GANT61, decreased the promoter activity in reporter assays. ΔNGLI2 (which lacks the repressor domain) was the most potent vector in activating the survivin promoter–reporter. Moreover, GANT61, a GLI1/2 inhibitor, repressed endogenous survivin protein and mRNA expression in most cells across a large panel of tumor cell lines. Chromatin immunoprecipitation showed GLI2 binding to the survivin promoter. The ectopic GLI2-evoked expression of endogenous survivin was observed in normal human fibroblasts. GANT61 decreased survivin level in nude mice tumors, mimicking the activity of GANT61 in cultured cells. The immunohistochemistry and double immunofluorescence of human tumors revealed a correlation between the tissue regions showing high GLI2 and survivin positivity. Thus, these results demonstrated that survivin is a classical transcriptional target of GLI2, a Hedgehog pathway signaling effector. This potentially reflects the high expression of survivin in human tumor cells. As the Hedgehog pathway is upregulated in virtually all types of cancer cells, these findings substantially contribute to the explanation of uniform survivin expression in tumors as a potential target for the development of a more effective treatment of cancers through the inhibition of GLI2 to restrain survivin activity.
机译：Survivin是一种重要的抗凋亡蛋白，在肿瘤中表达，而在正常组织中，该蛋白的表达极低，这定义了survivin作为癌症基因的作用。 Survivin在肿瘤细胞中表现出多功能活性。然而，为何存活蛋白的表达急剧且总是局限于肿瘤组织尚不清楚。在这里，我们确定了survivin启动子中GLI转录因子的11个假定的共有结合位点，并表征了启动子的活性。 Hedgehog / GLI途径的抑制剂环巴胺和GANT61在报告基因检测中降低了启动子的活性。 ΔNGLI2（缺少阻遏物结构域）是激活survivin启动子-报告子的最有效载体。此外，GANT1 / 2抑制剂GANT61抑制了一大批肿瘤细胞系中大多数细胞的内源性survivin蛋白和mRNA表达。染色质免疫沉淀显示GLI2与survivin启动子结合。在正常人成纤维细胞中观察到异位GLI2引起的内源性survivin表达。 GANT61降低了裸鼠肿瘤中survivin的水平，模仿了培养细胞中GANT61的活性。人类肿瘤的免疫组织化学和双重免疫荧光揭示了显示高GLI2的组织区域与survivin阳性之间的相关性。因此，这些结果表明，survivin是GLI2（一种刺猬信号通路的效应物）的经典转录靶标。这可能反映了survivin在人肿瘤细胞中的高表达。由于Hedgehog通路在几乎所有类型的癌细胞中均上调，因此这些发现在很大程度上有助于解释肿瘤中均一的survivin表达，将其作为通过抑制GLI2抑制survivin活性来开发更有效治疗癌症的潜在目标。 。

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