Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions
Department of Cell Biology; Department of Cancer Biology; Department of Orthopedics and Physical Rehabilitation
Animals; Bone Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Core Binding Factor Alpha 1 Subunit; *Disease Progression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Male; Mice; Mice, SCID; Osteoblasts; Osteoclasts; Osteolysis; Prostatic Neoplasms; Tibia; Tissue Array Analysis; Transcriptional Activation
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.
DOI of Published Version
Oncogene. 2010 Feb 11;29(6):811-21. Epub 2009 Nov 16. Link to article on publisher's site
Akech, Jacqueline; Wixted, John J.; Bedard, Krystin; Van der Deen, Margaretha; Hussain, Sadiq; Guise, T. A.; Van Wijnen, Andre J.; Stein, Janet L.; Languino, Lucia R.; Altieri, Dario C.; Pratap, Jitesh; Keller, E.; Stein, Gary S.; and Lian, Jane B., "Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions" (2010). Stein, Stein, Lian, vanWijnen Lab Publications. 22.