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

Francisco Villanueva, Hector Araya, Pedro Briceño, Nelson Varela, Andres Stevenson, Sofia Jerez, Fabian Tempio, Jonas Chnaiderman, Carola Perez, Milena Villarroel, Emma Concha, Farzaneh Khani, Roman Thaler, Flavio Salazar-Onfray, Gary S. Stein, Andre J. van Wijnen, Mario Galindo

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)13659-13679
Number of pages21
JournalJournal of Cellular Physiology
Volume234
Issue number8
DOIs
StatePublished - Aug 2019

Keywords

  • cancer
  • cell adhesion
  • metastasis
  • osteopontin
  • osteosarcoma

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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    Villanueva, F., Araya, H., Briceño, P., Varela, N., Stevenson, A., Jerez, S., Tempio, F., Chnaiderman, J., Perez, C., Villarroel, M., Concha, E., Khani, F., Thaler, R., Salazar-Onfray, F., Stein, G. S., van Wijnen, A. J., & Galindo, M. (2019). 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. Journal of Cellular Physiology, 234(8), 13659-13679. https://doi.org/10.1002/jcp.28046