Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma
Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma
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胰岛素样生长因子结合蛋白5抑制人骨肉瘤的肿瘤生长和转移
DOI：
10.1038/onc.2011.97
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发表时间：
2011-09-01
期刊：
影响因子：
8
通讯作者：
Luu, H. H.
中科院分区：
文献类型：
--
作者：
Su, Y.;Wagner, E. R.;Luu, H. H.
骨肉瘤(OS)是最常见的骨原发恶性肿瘤。迫切需要确定导致OS发展和转移机制知之甚少的事件。本研究的目的是确定和描述一种新的OS进展的标志物。我们已经建立并鉴定了一种高转移性的OS亚系，它是从转移率较低的人MG63系通过裸鼠体内注射连续传代而来的。对亲本MG63、高转移的MG63.2亚系以及相应的原发肿瘤和肺转移瘤的芯片分析显示，胰岛素样生长因子结合蛋白5(IGfbp5)是转移亚系中显著下调的基因之一。对20个感兴趣基因的确证定量RT-PCR结果显示，Igfbp5的表达差异最大，因此被选为进一步研究的基因之一。腺病毒介导的Igfbp5在MG63和MG63.2细胞系以及其他独立于我们的MG63细胞系的OS细胞系(143B和MNNG/HOS)中的过表达和下调被用来检测Igfbp5的作用。我们发现在体外过表达Igfbp5抑制了OS细胞的增殖、迁移和侵袭。此外，Igfbp5过表达促进细胞凋亡和细胞周期停滞于G1期。在异种原位移植动物模型中，过表达Igfbp5抑制了OS肿瘤的生长和肺转移。相反，siRNA介导的Igfbp5基因敲除促进了OS肿瘤的生长和体内的肺转移。患者配对的原发和转移性OS样本的免疫组织化学染色显示，转移性OS中Igfbp5表达降低。这些结果提示：1)Igfbp5作为一种新的标志物在OS的发病机制中具有重要作用；2)Igfbp5功能的丧失可能与OS中更多的转移表型有关。Oncogene(2011年)30,3907-3917；doi：10.1038/onc.2011.97；2011年4月4日在线发布
Osteosarcoma (OS) is the most common primary malignancy of bone. There is a critical need to identify the events that lead to the poorly understood mechanism of OS development and metastasis. The goal of this investigation is to identify and characterize a novel marker of OS progression. We have established and characterized a highly metastatic OS subline that is derived from the less metastatic human MG63 line through serial passages in nude mice via intratibial injections. Microarray analysis of the parental MG63, the highly metastatic MG63.2 subline, as well as the corresponding primary tumors and pulmonary metastases revealed insulin-like growth factor binding protein 5 (IGFBP5) to be one of the significantly downregulated genes in the metastatic subline. Confirmatory quantitative RT-PCR on 20 genes of interest demonstrated IGFBP5 to be the most differentially expressed and was therefore chosen to be one of the genes for further investigation. Adenoviral mediated overexpression and knockdown of IGFBP5 in the MG63 and MG63.2 cell lines, as well as other OS lines (143B and MNNG/HOS) that are independent of our MG63 lines, were employed to examine the role of IGFBP5. We found that overexpression of IGFBP5 inhibited in vitro cell proliferation, migration and invasion of OS cells. Additionally, IGFBP5 overexpression promoted apoptosis and cell cycle arrest in the G1 phase. In an orthotopic xenograft animal model, overexpression of IGFBP5 inhibited OS tumor growth and pulmonary metastases. Conversely, siRNA-mediated knockdown of IGFBP5 promoted OS tumor growth and pulmonary metastases in vivo. Immunohistochemical staining of patient-matched primary and metastatic OS samples demonstrated decreased IGFBP5 expression in the metastases. These results suggest 1) a role for IGFBP5 as a novel marker that has an important role in the pathogenesis of OS, and 2) that the loss of IGFBP5 function may contribute to more metastatic phenotypes in OS. Oncogene (2011) 30, 3907-3917; doi:10.1038/onc.2011.97; published online 4 April 2011