MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), amplified on chromosome 9, collaborate with p53 deficiency in mouse osteosarcoma progression.
MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), amplified on chromosome 9, collaborate with p53 deficiency in mouse osteosarcoma progression.
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DOI：
10.1158/0008-5472.can-08-2929
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Donehower LA
中科院分区：
文献类型：
--
作者：
Ma O;Cai WW;Zender L;Dayaram T;Shen J;Herron AJ;Lowe SW;Man TK;Lau CC;Donehower LA
骨肉瘤是原发性骨恶性肿瘤，尤其影响青少年和年轻人，可导致身体虚弱，有时甚至死亡。作为人类骨肉瘤的模型，我们一直在研究p53+/−小鼠，它们发生骨肉瘤的频率很高。为了发现在骨肉瘤形成过程中与p53缺失相关的基因，我们整合了阵列比较基因组杂交、小鼠和人骨肉瘤的微阵列表达分析以及功能分析。在这项研究中，我们在小鼠p53+/−骨肉瘤中发现了7个拷贝数增加和减少的常见区域，但主要集中在小鼠染色体9A1上的复发性扩增事件。该扩增子与在许多人类肿瘤类型中发现的类似的染色体11q22扩增子是同源的。该扩增子上的三个基因，基质金属蛋白酶基因MMP13，以及抗凋亡基因Birc2 （cIAP1）和Birc3 （cIAP2）在小鼠和人骨肉瘤中表达升高。我们利用慢病毒shRNA载体转导的克隆性骨肉瘤细胞系开展了一项功能分析，表明MMP13、Birc2或Birc3的下调可导致移植到免疫缺陷受体小鼠体内的肿瘤生长减少。这些实验表明，MMP13的高表达提高了骨肉瘤细胞的存活率，Birc2和Birc3也提高了细胞存活率，但仅在染色体9A1扩增子的骨肉瘤细胞中。我们得出结论，抗凋亡基因Birc2和Birc3是染色体9A1扩增子中潜在的致癌驱动因素。
Osteosarcoma is the primary malignant cancer of bone and particularly affects adolescents and young adults, causing debilitation, and sometimes death. As a model for human osteosarcoma we have been studying p53+/− mice, which develop osteosarcoma at high frequency. To discover genes that cooperate with p53 deficiency in osteosarcoma formation we have integrated array comparative genomic hybridization, microarray expression analyses in mouse and human osteosarcomas, and functional assays. In this study we found seven frequent regions of copy number gain and loss in the mouse p53+/− osteosarcomas, but have focused on a recurrent amplification event on mouse chromosome 9A1. This amplicon is syntenic with a similar chromosome 11q22 amplicon identified in a number of human tumor types. Three genes on this amplicon, the matrix metalloproteinase gene MMP13, and the anti-apoptotic genes Birc2 (cIAP1), and Birc3 (cIAP2) show elevated expression in mouse and human osteosarcomas. We developed a functional assay using clonal osteosarcoma cell lines transduced with lentiviral shRNA vectors to show that downregulation of MMP13, Birc2, or Birc3 resulted in reduced tumor growth when transplanted into immunodeficient recipient mice. These experiments revealed that high MMP13 expression enhances osteosarcoma cell survival and that Birc2 and Birc3 also enhance cell survival, but only in osteosarcoma cells with the chromosome 9A1 amplicon. We conclude that the anti-apoptotic genes Birc2 and Birc3 are potential oncogenic drivers in the chromosome 9A1 amplicon.