Role of GLI2 in the growth of human osteosarcoma
Role of GLI2 in the growth of human osteosarcoma
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DOI：
10.1002/path.2880
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发表时间：
2011-06-01
影响因子：
7.3
通讯作者：
Setoguchi, Takao
中科院分区：
文献类型：
--
作者：
Nagao, Hiroko;Ijiri, Kosei;Setoguchi, Takao
Hedgehog通路在胚胎发育中起组织者的作用。在各种类型的恶性肿瘤中已经报道了Hedgehog通路的异常激活。GLI2转录因子是Hedgehog通路的关键介质，但其在肿瘤发生中的作用尚不清楚。为了确定GLI2在骨肉瘤中的作用，我们用活检组织检测了它的实时PCR表达。为了研究GLI2的功能，我们评估了GLI2敲除后骨肉瘤细胞的生长和细胞周期。为了研究GLI2激活的影响，我们检测了强制表达GLI2后间充质干细胞的生长和细胞周期。我们发现GLI2在人骨肉瘤活检标本中异常过表达。RNA干扰GLI2敲低可阻止骨肉瘤生长和非锚定生长。GLI2的下调促进了骨肉瘤细胞在G(1)期的阻滞，并伴有细胞周期促进因子cyclin D1、SKP2和磷酸化Rb的蛋白表达降低。另一方面，GLI2的敲低增加了p21（cip1）的表达。此外，GLI2的过表达促进了间充质干细胞的增殖，加速了它们的细胞周期进程。最后，对小鼠异种移植模型的评估表明，GLI2敲低抑制了裸鼠骨肉瘤的生长。我们的研究结果表明，抑制GLI2可能是骨肉瘤患者的一种有效治疗方法。版权所有(C) 2011英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
The Hedgehog pathway functions as an organizer in embryonic development. Aberrant activation of the Hedgehog pathway has been reported in various types of malignant tumours. The GLI2 transcription factor is a key mediator of Hedgehog pathway but its contribution to neoplasia is poorly understood. To establish the role of GLI2 in osteosarcoma, we examined its expression by real-time PCR using biopsy tissues. To examine the function of GLI2, we evaluated the growth of osteosarcoma cells and their cell cycle after GLI2 knockdown. To study the effect of GLI2 activation, we examined mesenchymal stem cell growth and the cell cycle after forced expression of GLI2. We found that GLI2 was aberrantly over-expressed in human osteosarcoma biopsy specimens. GLI2 knockdown by RNA interferences prevented osteosarcoma growth and anchorage-independent growth. Knockdown of GLI2 promoted the arrest of osteosarcoma cells in G(1) phase and was accompanied by reduced protein expression of the cell cycle accelerators cyclin D1, SKP2 and phosphorylated Rb. On the other hand, knockdown of GLI2 increased the expression of p21(cip1). In addition, over-expression of GLI2 promoted mesenchymal stem cell proliferation and accelerated their cell cycle progression. Finally, evaluation of mouse xenograft models showed that GLI2 knockdown inhibited the growth of osteosarcoma in nude mice. Our findings suggest that inhibition of GLI2 may represent an effective therapeutic approach for patients with osteosarcoma. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.