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Over‐expression of parathyroid hormone Type 1 receptor confers an aggressive phenotype in osteosarcoma
Author(s) -
Yang Rui,
Hoang Bang H.,
Kubo Tadahiko,
Kawano Hirotaka,
Chou Alexander,
Sowers Rebecca,
Huvos Andrew G.,
Meyers Paul A.,
Healey John H.,
Gorlick Richard
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22749
Subject(s) - osteosarcoma , autocrine signalling , gene knockdown , parathyroid hormone , paracrine signalling , cancer research , biology , cell culture , transfection , medicine , endocrinology , downregulation and upregulation , receptor , microbiology and biotechnology , gene , calcium , biochemistry , genetics
Osteosarcoma is the most common primary bone malignancy in children and is associated with rapid bone growth. Parathyroid hormone‐related peptide (PTHrP) signaling via parathyroid hormone Type 1 receptor (PTHR1) is important for skeletal development and is involved in bone metastases in other tumors. The aim of this study was to investigate the status of PTHrP/PTHR1 and its possible role in osteosarcoma. In a preliminary screening, a higher level of PTHR1 mRNA, but not PTHrP, was found in 4 osteosarcoma xenografts as compared with 4 standard cell lines, or 5 patient derived cell lines ( p < 0.05) using quantitative RT‐PCR. It was therefore extended to 55 patient specimens, in which a significantly higher level of PTHR1 mRNA was detected in metastatic or relapsed samples than those from primary sites ( p < 0.01). Cell behavior caused by PTHR1 overexpression was further studied in vitro using PTHR1 transfected HOS cell line as a model. Over‐expression of PHTR1 resulted in increased proliferation, motility and Matrigel invasion without addition of exogenous PTHrP suggesting an autocrine effect. Importantly, the aggressiveness in PTHR1‐expressing cells was completely reversed by RNAi mediated gene knockdown. In addition, PTHR1 over‐expression led to delayed osteoblastic differentiation and upregulation of genes involved in extracellular matrix production, such as TGF‐β1 and connective tissue growth factor. When cocultured with bone marrow derived monocytes, PTHR1 transfected HOS cells induced a greater number of osteoclasts. This study suggests that PTHR1 over‐expression may promote osteosarcoma progression by conferring a more aggressive phenotype, and forming a more favorable microenvironment. © 2007 Wiley‐Liss, Inc.