CD49b inhibits osteogenic differentiation and plays an important role in osteosarcoma progression
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Tingting Ren1,2, Sajida Piperdi2, Pratistha Koirala2, Amy Park2, Wendong Zhang2, Daria Ivenitsky2, Yidan Zhang1,2, Esperanza Villanueva-Siles3, Douglas S. Hawkins4, Michael Roth2 and Richard Gorlick5
1Department of Orthopedics, Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, China
2Department of Pediatrics, Division of Hematology/Oncology, The Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
3Department of Pathology, Montefiore Medical Center, Bronx, NY, USA
4Department of Pediatrics, Division of Hematology/Oncology, Seattle Children’s Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA
5Department of Pediatrics, Children’s Cancer Hospital, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Richard Gorlick, email: [email protected]
Keywords: CD49b, osteosarcoma, osteogenic differentiation, mesenchymal stem cells, osteoblasts
Received: June 03, 2017 Accepted: August 23, 2017 Published: September 23, 2017
Osteosarcoma is a cancer whose cell of origin lies in the differentiation pathway between the mesenchymal stem cell (MSC) and the osteoblast (OB). In this study, we sought to determine if surface markers associated with osteoblastic differentiation are involved in osteosarcoma progression. cDNA expression arrays were performed on MSCs and osteoblasts to identify differentially expressed genes. The specificity of candidate genes for osteoblast differentiation was assessed through time course experiments in differentiation media with confirmation utilizing CD49b transfected MSCs. In addition, CD49b was transfected into osteosarcoma cell lines to determine its impact on cell proliferation, motility, and invasion. Finally, the expression of CD49b was assessed in osteosarcoma patient samples and correlated with survival outcomes. cDNA expression arrays identified a list of genes differentially expressed between MSCs and osteoblasts with a subset of those genes encoding cell surface proteins. Three genes were selected for further analysis, based on qPCR validation, but only CD49b was selective for osteoblastic differentiation. Forced expression of CD49b in MSCs led to delayed osteoblastic differentiation. Down-regulation of CD49b expression in osteosarcoma cell lines resulted in inhibition of their migration and invasion capacity. CD49b expression in osteosarcoma patients was associated with presence of metastases and inferior 5 year overall survival (31.4% vs. 57.4%, p=0.03). Surface proteins involved in osteosarcoma cell differentiation, such as CD49b, have the potential to serve as prognostic biomarkers, and may lead to the identification of new therapeutic targets.
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