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BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line.

ABSTRACT: Previously, based on high ALDH activity, we showed that cancer stem cells (CSCs) could be identified as ALDH(br) cells from an aggressive human osteosarcoma OS99-1 cell line. In this study, we evaluate the impact of BMP-2 on CSCs.Three types of BMP receptors were expressed in freshly sorted ALDH(br) cells. In vitro, growth of the sorted ALDH(br) cells was inhibited by BMP-2. Using RT-PCR analysis, BMP-2 was found to down-regulate the expression of embryonic stem cell markers Oct3/4, Nanog, and Sox-2, and up-regulate the transcription of osteogenic markers Runx-2 and Collagen Type I. In vivo, all animals receiving ALDH(br) cells treated with BMP-2 did not form significant tumors, while untreated ALDH(br) cells developed large tumor masses in NOD/SCID mice. Immunostaining confirmed few Ki-67 positive cells were present in the sections of tumor containing ALDH(br) cells treated with BMP-2. These results suggest that BMP-2 suppresses tumor growth by reducing the gene expression of tumorigenic factors and inducing the differentiation of CSCs in osteosarcoma. BMP-2 or BMP-2-mimetic drugs, if properly delivered to tumor and combined with traditional therapies, may therefore provide a new therapeutic option for treatment of osteosarcoma.

SUBMITTER: Wang L

PROVIDER: S-EPMC3230314 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line.

Wang Lin L Park Paul P Zhang Huina H La Marca Frank F Claeson Amy A Valdivia Juan J Lin Chia-Ying CY

Cancer biology & therapy 20110301 5

Previously, based on high ALDH activity, we showed that cancer stem cells (CSCs) could be identified as ALDH(br) cells from an aggressive human osteosarcoma OS99-1 cell line. In this study, we evaluate the impact of BMP-2 on CSCs.Three types of BMP receptors were expressed in freshly sorted ALDH(br) cells. In vitro, growth of the sorted ALDH(br) cells was inhibited by BMP-2. Using RT-PCR analysis, BMP-2 was found to down-regulate the expression of embryonic stem cell markers Oct3/4, Nanog, and S ...[more]

PMID: 21178508

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Project description:Osteosarcoma (OS) is a primary malignant tumor of bone occurring in young adults. OS stem cells (OSCs) play an important role in the occurrence, growth, metastasis, drug resistance and recurrence of OS. CD133 is an integral membrane glycoprotein, which has been identified as an OSC marker. However, the mechanisms of metastasis, chemoresistance, and progression in CD133(+) OSCs need to be further explored. In this study, we aim to explore differences in miRNA levels between CD133(+) and CD133(-) cells from the MG-63 cell line. We found 20 differentially expressed miRNAs (DEmiRNAs) (16 upregulated and 4 downregulated) in CD133(+) cells compared with CD133(-) cells. Hsa-miR-4485-3p, hsa-miR-4284 and hsa-miR-3656 were the top three upregulated DEmiRNAs, while hsa-miR-487b-3p, hsa-miR-493-5p and hsa-miR-431-5p were the top three downregulated DEmiRNAs. In addition, RT-PCR analysis confirmed that the expression levels of hsa-miR-4284, hsa-miR-4485-3p and hsa-miR-3656 were significantly increased, while the expression levels of hsa-miR-487b-3p, hsa-miR-493-5p, and hsa-miR-431-5p were significantly decreased in CD133(+) cells compared with CD133(-) cells. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that predicted or validated target genes for all 20 DEmiRNAs or the selected 6 DEmiRNAs participated in the "PI3K-Akt signaling pathway," "Wnt signaling pathway," "Rap1 signaling pathway," "Cell cycle" and "MAPK signaling pathway". Among the selected six DEmiRNAs, miR-4284 was especially interesting. MiR-4284 knockdown significantly reduced the sphere forming capacity of CD133(+) OS cells. The number of invasive CD133(+) OS cells was markedly decreased after miR-4284 knockdown. In addition, miR-4284 knockdown increased the p-β-catenin levels in CD133(+) OS cells. In conclusion, RNA-seq analysis revealed DEmiRNAs between CD133(+) and CD133(-) cells. MiRNAs might play significant roles in the function of OSCs and could serve as targets for OS treatment. MiR-4284 prompted the self-renewal and invasion of OSCs. The function of miR-4284 might be associated with the Wnt signaling pathway.

Dataset Information

BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line.

Publications

BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line.

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