title: CCN3 promotes prostate cancer bone metastasis by modulating the tumor-bone microenvironment through RANKL-dependent pathway.
abstract: Bone metastasis in patient with advanced-stage prostate cancer, the most commonly diagnosed malignancy in Western countries, increases the risk of intractable bone pain. The nephroblastoma overexpressed (NOV/CCN3) gene, a member of the CCN gene family, is responsible for the secretion of CCN3, a matrix-associated protein involved in many cellular functions. However, the role of CCN3 in prostate cancer metastasis to bone is poorly understood. CCN3 was found to be highly expressed in bone metastasis patients and positively correlated with malignancy in human prostate cancer cells. Prostate cancer conditioned medium-induced osteoclast differentiation was inhibited by neutralizing antibody against CCN3. Specifically, CCN3 was found to induce osteoclastogenesis through the receptor activator of NF-κB ligand (RANKL)-dependent pathway, and the focal adhesion kinase/Akt/p38/NF-κB signal pathway was found to be involved in CCN3-mediated receptor activator of NF-κB expression and RANKL-dependent osteoclastogenesis. In contrast, osteoblasts were observed to play an important role in osteoclast differentiation by paracrine manner, with treatment of osteoblasts with CCN3 found to change the RANKL (osteoclastogenesis):OPG (antiosteoclastogenesis) ratio. Compared with parental PC3 cells, highly invasive PC3-I3 cells markedly enhanced osteoclast activity and bone metastasis in vivo. These results indicate that CCN3 can be used as a novel therapeutic target in the prevention of bone metastasis of prostate cancer.
authors.affiliation: Department of Life Sciences, National Chung Hsing University, No 250, Kuo-Kuang Rod, Taichung, Taiwan.
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Chen
authors.forename: Hsu-Chen
authors.initials: HC
authors.lastname: Cheng
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism; D001859:Bone Neoplasms / Q000556:secondary*; D001862:Bone Resorption; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D055514:Nephroblastoma Overexpressed Protein / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D057134:Antibodies, Neutralizing; C526319:CCN3 protein, human; D017077:Culture Media, Conditioned; D016328:NF-kappa B; D055514:Nephroblastoma Overexpressed Protein; D053245:RANK Ligand; C505688:TNFSF11 protein, human