Discoidin domain receptor 2 facilitates prostate cancer bone metastasis via regulating parathyroid hormone-related protein.
Prostate cancer frequently metastasizes to the skeleton but the underlying mechanism remains largely undefined. Discoidin domain receptor 2 (DDR2) is a member of receptor tyrosine kinase (RTK) family and is activated by collagen binding. This study aimed to investigate the function and detailed mechanism of DDR2 in prostate cancer bone dissemination. Herein we found that DDR2 was strongly expressed in bone-metastatic prostate cancer cells and tissues compared to that in normal controls. Enhanced expression of constitutively activated DDR2 led to elevation in motility and invasiveness of prostate cancer cells, whereas knockdown of DDR2 through specific shRNA caused a dramatic repression. Knockdown of DDR2 in prostate cancer cells resulted in significant decrease in the proliferation, differentiation and function of osteoblast. Over-expression of DDR2 in prostate cancer cells resulted in notable acceleration of osteoclast differentiation and bone resorption, whereas knockdown of DDR2 exhibited the opposite effects. An intrabone injection bone metastasis animal model demonstrated that DDR2 promoted osteolytic metastasis in vivo. Molecular evidence demonstrated that DDR2 regulated the expression, secretion, and promoter activity of parathyroid hormone-related protein (PTHrP), via modulating Runx2 phosphorylation and transactivity. DDR2 was responsive to TGF-β and involved in TGF-β-mediated osteoclast activation and bone resorption. In addition, DDR2 facilitated prostate cancer cells adhere to type I collagen. This study reveals for the first time that DDR2 plays an essential role in prostate cancer bone metastasis. The mechanism disclosure may provide therapeutic targets for the treatment of prostate cancer.
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, PR China.
Zhang
Z
Yan
Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, PR China.
Su
S
Jin
Department of Biopharmaceutics, The Fourth Military Medical University, Xi'an, PR China.
Zhang
Z
Wei
Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, PR China.
Hou
H
Huilian
Department of Orthopaedics, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, PR China.
Yin
Y
Zhanhai
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, PR China.
Teng
T
Yue
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, PR China.
Li
L
Juan
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, PR China.
Li
L
Jing
Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, PR China.
Yao
Y
Libo
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, PR China.
Li
L
Xu
D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014945:Wound Healing
D024042:Collagen Type I; D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011975:Receptors, Mitogen; D016212:Transforming Growth Factor beta; D008156:Luciferases; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases
Bone metastasis; DDR2; PTHrP; Prostate cancer; Runx2