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

Ma, O., Cai, W. W., Zender, L., Dayaram, T., Shen, J. H., Herron, A. J., Lowe, S. W., Man, T. K., Lau, C. C., Donehower, L. A. (March 2009) MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), Amplified on Chromosome 9, Collaborate with p53 Deficiency in Mouse Osteosarcoma Progression. Cancer Res, 69 (6). pp. 2559-2567. ISSN 0008-5472

URL: http://www.ncbi.nlm.nih.gov/pubmed/19276372
DOI: 10.1158/0008-5472.CAN-08-2929

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 several human tumor types. Three genes on this amplicon, the matrix metalloproteinase gene MMP13 and the antiapoptotic genes Birc2 (cI4P1) and Birc3 (cIAP2), show elevated expression in mouse and human osteosarcomas. We developed a functional assay using clonal osteosarcoma cell lines transduced with lentiviral short hairpin RNA vectors to show that down-regulation 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 antiapoptotic genes Birc2 and Birc3 are potential oncogenic drivers in the chromosome 9A1 amplicon. [Cancer Res 2009;69(6):2559-67]

Item Type: Paper
Uncontrolled Keywords: COMPARATIVE GENOMIC HYBRIDIZATION ALPHA-DEPENDENT APOPTOSIS SQUAMOUS-CELL CARCINOMA YES-ASSOCIATED PROTEIN MATRIX METALLOPROTEINASES COLLAGENASE-3 MMP-13 PANCREATIC-CANCER INHIBITOR EXPRESSION UBIQUITINATION
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: 15 March 2009
Date Deposited: 20 Feb 2013 17:13
Last Modified: 20 Feb 2013 17:13
PMCID: PMC2663905
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27416

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