MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), amplified on chromosome 9, collaborate with p53 deficiency in mouse osteosarcoma progression.
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 (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 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.
Ma
Ou
O
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
Cai
Wei-Wen
WW
Zender
Lars
L
Dayaram
Tajhal
T
Shen
Jianhe
J
Herron
Alan J
AJ
Lowe
Scott W
SW
Man
Tsz-Kwong
TK
Lau
Ching C
CC
Donehower
Lawrence A
LA
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics*; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005784:Gene Amplification; D042822:Genomic Instability; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000172:deficiency / Q000235:genetics*; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; D010750:Phosphoproteins; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494834:Birc2 protein, mouse; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053509:Matrix Metalloproteinase 13