The Hedgehog Pathway Transcription Factor GLI1 Promotes Malignant Behavior of Cancer Cells by Up-regulating Osteopontin
The Hedgehog Pathway Transcription Factor GLI1 Promotes Malignant Behavior of Cancer Cells by Up-regulating Osteopontin
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DOI：
10.1074/jbc.m109.021949
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发表时间：
2009-08-21
影响因子：
4.8
通讯作者：
Shevde, Lalita A.
中科院分区：
文献类型：
--
作者：
Das, Shamik;Harris, Lillianne G.;Shevde, Lalita A.
Hedgehog（Hh）信号传导作为发育途径的作用已经被充分确立。最近的几项研究表明，该途径在多种癌症中发挥作用。在这项研究中，我们报告GLI1和骨桥蛋白（OPN）的表达随着黑色素瘤从原发性皮肤癌到转移性黑色素瘤的进展而逐渐增加。我们进一步确定OPN是GLI1的直接转录靶点。我们已经观察到，OPN表达在Hh配体的存在下被刺激，并且在Smoothened（SMO）抑制剂环巴胺的存在下被抑制。GLI1的转录沉默对OPN表达产生负面影响，并损害癌细胞在体外增殖、迁移和侵袭的能力，并干扰其作为异种移植物生长和在裸鼠中自发转移的能力。这些改变的属性可以通过在GLI1沉默的细胞中重新表达OPN来挽救，这表明OPN是活性GLI1信号传导的关键下游效应物。我们的观察使我们得出结论，GLI1介导的OPN上调促进癌细胞的恶性行为。
The role of Hedgehog (Hh) signaling as a developmental pathway is well established. Several recent studies have implicated a role for this pathway in multiple cancers. In this study we report that expression of GLI1 and osteopontin (OPN) increase progressively with the progression of melanoma from primary cutaneous cancer to metastatic melanoma in clinically derived specimens. We have further determined that OPN is a direct transcriptional target of GLI1. We have observed that OPN expression is stimulated in the presence of Hh ligands and inhibited in the presence of the Smoothened (SMO) inhibitor, cyclopamine. Transcriptional silencing of GLI1 negatively impacts OPN expression and compromises the ability of cancer cells to proliferate, migrate, and invade in vitro and interferes with their ability to grow as xenografts and spontaneously metastasize in nude mice. These altered attributes could be rescued by re-expressing OPN in the GLI1-silenced cells, suggesting that OPN is a critical downstream effector of active GLI1 signaling. Our observations lead us to conclude that the GLI1-mediated up-regulation of OPN promotes malignant behavior of cancer cells.