MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), Amplified on Chromosome 9, Collaborate with p53 Deficiency in Mouse Osteosarcoma Progression

Abstract

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.Requests for reprints: Lawrence A.

A molecular signature of normal breast epithelial and stromal cells from Li-Fraumeni syndrome mutation carriers

“…BIRC3, also known as cIAP2, plays an important role in promoting cell survival and inhibiting apoptosis [35]. The increased expression of BIRC3 found in our analyses of LFS breast epithelial and stromal cells, and the normalization of expression with TP53 conformational rescue drugs, are consistent with an important role for BIRC3 anti-apoptotic signals in LFS initiated cells, and with recent findings that BIRC3 can drive tumorigenesis on a p53-deficient background in mouse osteosarcoma [36]. Importantly, the presence of the BIRC3 signature suggests a potentially relevant early detection biomarker for TP53 haploinsufficiency that could facilitate cellular transformation in LFS preneoplastic cells, and be a potential chemopreventative drug target.…”

Mammalian Sterile 20–like Kinase 1 Suppresses Lymphoma Development by Promoting Faithful Chromosome Segregation

“…Yap1 upregulation in spontaneous tumors from p53 À/À Mst1 þ/þ mice have been previously observed by others using mammary epithelial cell tumors or osteosarcomas (47,48). Yap1 upregulation in p53 À/À Mst1 þ/þ tumors seems to reflect an acquisition of a selective advantage by the combined p53 loss and Yap1 upregulation through an unknown mechanism.…”

IL-17A/IL-17RA interaction promoted metastasis of osteosarcoma cells

“…1,2 OS is locally destructive and has a high metastatic potential. 2,3 OS metastasis appear most frequently in the lung and are the main cause of death for patients with OS.…”