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CD99 acts as an oncosuppressor in osteosarcoma
Maria Cristina Manara1, Ghislaine Bernard, Pier-Luigi Lollini
1Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, Bologna, 40136 Italy.
Abstract:
CD99 was recently reported to be under control of the osteoblast-specific transcription factor Cbfa1 (RUNX2) in osteoblasts, suggesting a role in the phato-physiology of these cells. No extensive information is available on the role(s) of this molecule in malignant phenotype, and osteosarcoma, in particular, has never been studied. We report that in 11 different cell lines and 17 clinical samples CD99 expression is either undetectable or very low. Being expressed in the normal counterpart, we tested the hypothesis that CD99 down-regulation may have a role in osteosarcoma development and progression. CD99-forced expression in two osteosarcoma cell lines significantly reduced resistance to anoikis, inhibited growth in anchorage independence as well as cell migration, and led to abrogation of tumorigenic and metastatic ability. Therefore, the molecule acts as a potent suppressor of malignancy in osteosarcoma. CD99 gene transfection induces caveolin-1 up-regulation and the two molecules were found to colocalize on the cell surface. Treatment with antisense oligonucleotides to caveolin-1 abrogates the effects of CD99 on migration. The findings point to an antioncogenic role for CD99 in osteosarcoma, likely through the regulation of caveolin-1 and inhibition of c-Src kinase activity.
Insights
CD99, a molecule controlled by RUNX2 in osteoblasts, acts as a potent suppressor of malignancy in osteosarcoma. Its forced expression inhibits tumor growth, metastasis, and anoikis resistance, suggesting an antioncogenic role.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- CD99's role in osteoblast physiology is linked to the transcription factor RUNX2.
- Limited information exists on CD99's function in malignant phenotypes, especially osteosarcoma.
- CD99 expression is significantly reduced or absent in osteosarcoma cell lines and clinical samples.
Purpose of the Study:
- To investigate the role of CD99 down-regulation in osteosarcoma development and progression.
- To determine if CD99 possesses tumor-suppressive properties in osteosarcoma.
- To elucidate the molecular mechanisms underlying CD99's potential antioncogenic effects.
Main Methods:
- Analysis of CD99 expression in osteosarcoma cell lines and clinical samples.
- Forced expression of CD99 in osteosarcoma cell lines.
- Assessment of anoikis resistance, anchorage-independent growth, cell migration, and tumorigenic/metastatic potential.
- Investigation of CD99's interaction with caveolin-1 and c-Src kinase.
Main Results:
- CD99 expression is low or undetectable in osteosarcoma.
- Forced CD99 expression suppressed anoikis resistance, anchorage-independent growth, and cell migration.
- CD99 overexpression abrogated tumorigenic and metastatic abilities in vivo.
- CD99 gene transfection induced caveolin-1 up-regulation and co-localization.
- Antisense oligonucleotides targeting caveolin-1 reversed CD99's effects on migration.
Conclusions:
- CD99 acts as a potent suppressor of malignancy in osteosarcoma.
- CD99's antioncogenic role is likely mediated through caveolin-1 up-regulation and c-Src kinase inhibition.
- CD99 down-regulation may contribute to osteosarcoma development and progression.
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