Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions
Open Access
- 16 November 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 29 (6), 811-821
- https://doi.org/10.1038/onc.2009.389
Abstract
Runx2, a bone-specific transcriptional regulator, is abnormally expressed in highly metastatic prostate cancer cells. Here, we identified the functional activities of Runx2 in facilitating tumor growth and osteolysis. Our studies show that negligible Runx2 is found in normal prostate epithelial and non-metastatic LNCaP prostate cancer cells. In the intra-tibial metastasis model, high Runx2 levels are associated with development of large tumors, increased expression of metastasis-related genes (MMP9, MMP13, VEGF, Osteopontin) and secreted bone-resorbing factors (PTHrP, IL8) promoting osteolytic disease. Runx2 siRNA treatment of PC3 cells decreased cell migration and invasion through Matrigel in vitro, and in vivo shRunx2 expression in PC3 cells blocked their ability to survive in the bone microenvironment. Mechanisms of Runx2 function were identified in co-culture studies showing that PC3 cells promote osteoclastogenesis and inhibit osteoblast activity. The clinical significance of these findings is supported by human tissue microarray studies of prostate tumors at stages of cancer progression, in which Runx2 is expressed in both adenocarcinomas and metastatic tumors. Together these findings indicate that Runx2 is a key regulator of events associated with prostate cancer metastatic bone disease.Keywords
This publication has 45 references indexed in Scilit:
- New wirings in the survivin networksOncogene, 2008
- Runx2 Transcriptional Activation of Indian Hedgehog and a Downstream Bone Metastatic Pathway in Breast Cancer CellsCancer Research, 2008
- CCL2 Protects Prostate Cancer PC3 Cells from Autophagic Death via Phosphatidylinositol 3-Kinase/AKT-dependent Survivin Up-regulationJournal of Biological Chemistry, 2008
- Histopathological Assessment of Prostate Cancer Bone Osteoblastic MetastasesJournal of Urology, 2008
- Androgen receptor–negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanismsJCI Insight, 2008
- The pathogenesis of the bone disease of multiple myelomaBone, 2008
- Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potentialProceedings of the National Academy of Sciences, 2007
- Dickkopf Homolog 1 Mediates Endothelin-1-Stimulated New Bone FormationMolecular Endocrinology, 2007
- Matrix metalloproteinases and tumor metastasisCancer and Metastasis Reviews, 2006
- New functions for the matrix metalloproteinases in cancer progressionNature Reviews Cancer, 2002