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The cancer-related transcription factor RUNX2 modulates expression and secretion of the matricellular protein osteopontin in osteosarcoma cells to promote adhesion to endothelial pulmonary cells and lung metastasis.
- Source :
-
Journal of cellular physiology [J Cell Physiol] 2019 Aug; Vol. 234 (8), pp. 13659-13679. Date of Electronic Publication: 2019 Jan 13. - Publication Year :
- 2019
-
Abstract
- Osteosarcomas are bone tumors that frequently metastasize to the lung. Aberrant expression of the transcription factor, runt-related transcription factor 2 (RUNX2), is a key pathological feature in osteosarcoma and associated with loss of p53 and miR-34 expression. Elevated RUNX2 may transcriptionally activate genes mediating tumor progression and metastasis, including the RUNX2 target gene osteopontin (OPN/SPP1). This gene encodes a secreted matricellular protein produced by osteoblasts to regulate bone matrix remodeling and tissue calcification. Here we investigated whether and how the RUNX2/OPN axis regulates lung metastasis of osteosarcoma. Importantly, RUNX2 depletion attenuates lung metastasis of osteosarcoma cells in vivo. Using next-generation RNA-sequencing, protein-based assays, as well as the loss- and gain-of-function approaches in selected osteosarcoma cell lines, we show that osteopontin messenger RNA levels closely correlate with RUNX2 expression and that RUNX2 controls the levels of secreted osteopontin. Elevated osteopontin levels promote heterotypic cell-cell adhesion of osteosarcoma cells to human pulmonary microvascular endothelial cells, but not in the presence of neutralizing antibodies. Collectively, these findings indicate that the RUNX2/OPN axis regulates the ability of osteosarcoma cells to attach to pulmonary endothelial cells as a key step in metastasis of osteosarcoma cells to the lung.<br /> (© 2019 Wiley Periodicals, Inc.)
- Subjects :
- Animals
Bone Neoplasms pathology
Cell Adhesion physiology
Cell Line, Tumor
Endothelial Cells metabolism
Heterografts
Humans
Lung metabolism
Lung pathology
Lung Neoplasms secondary
Mice
Mice, Inbred NOD
Mice, SCID
Osteosarcoma secondary
Bone Neoplasms metabolism
Core Binding Factor Alpha 1 Subunit metabolism
Gene Expression Regulation, Neoplastic physiology
Neoplasm Invasiveness
Osteopontin metabolism
Osteosarcoma metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4652
- Volume :
- 234
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of cellular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 30637720
- Full Text :
- https://doi.org/10.1002/jcp.28046