Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions

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 demonstrate 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, IL-8) 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 demonstrating 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, where 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.

Transcription factor Runx2 is a regulator of epithelial–mesenchymal transition and invasion in thyroid carcinomas

“…8,20 In breast carcinoma cells, expression of Runx2 is shown to be important in the positive regulation of angiogenic factors, and Runx2-regulated MMPs are functionally related to the invasion properties of breast cancer cells. 29,30 Likewise, our current study demonstrated that Runx2 expression is involved with positive regulation of angiogenic factors (VEGFA, VEGFC), MMP2 and EMTrelated molecules (SNAI2, SNAI3, TWIST1) in thyroid carcinoma.…”

“…[23][24][25] Enhanced Runx2 expression in prostate cancer is associated with disease progression including higher Gleason scores. 8 In breast cancers with a high labeling index of Runx2, the clinical outcome of the breast cancer was worse; Runx2 is used as an independent prognostic factor in these patients. 23 An increasing number of studies have suggested oncogenic functions of Runx2 in carcinoma cells.…”

“…Runx2 promotes the metastatic ability of cancer cells by enhancing the secretion of various types of matrix metalloproteinases (MMPs) and VEGF, a key angiogenic factor. [8][9][10] Furthermore, upregulation of Runx2 induces EMT-related molecules such as SOX9, Snail2/Slug/SNAI2 and SMAD3 that potentially enhance invasion of cancer cells. 11,12 In thyroid cancers, overexpression of EMT-related proteins, including Runx2, has been reported; however, little is known about the expression profile of the Runx family and their biological functions in thyroid carcinogenesis.…”

Homing of Cancer Cells to the Bone

“…Inhibition of RUNX2 in MDA-MB-231 cells transplanted to bone decreases tumorigenesis and prevents osteolysis [140]. In the intra-tibial metastasis model, high RUNX2 levels is associated with development of large tumors and with increased expression of metastasis-related genes (MMP9, MMP13, VEGF, OPN) and secreted bone-resorbing factors (PTHrP, IL-8) [141].…”

“…In co-cultures RUNX2 promotes osteoclastogenesis in PC3 cells and inhibits osteoblast activity. [141]. Induction of RUNX2 in C4-2B cells enhances their invasiveness and promotes cellular quiescence by blocking the G1/S phase transition during cell cycle progression [142].…”