Over-expression of parathyroid hormone Type 1 receptor confers an aggressive phenotype in osteosarcoma Journal Article
| Authors: | Yang, R.; Hoang, B. H.; Kubo, T.; Kawano, H.; Chou, A.; Sowers, R.; Huvos, A. G.; Meyers, P. A.; Healey, J. H.; Gorlick, R. |
| Article Title: | Over-expression of parathyroid hormone Type 1 receptor confers an aggressive phenotype in osteosarcoma |
| Abstract: | 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 overexpression 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. |
| Keywords: | osteosarcoma; signal transduction; controlled study; human cell; major clinical study; bone metastasis; cell proliferation; phenotype; cell function; gene overexpression; metastasis; reverse transcription polymerase chain reaction; cancer screening; rna interference; cell differentiation; cancer cell culture; extracellular matrix; genetic transfection; xenograft; messenger rna; reverse transcriptase polymerase chain reaction; rna, messenger; quantitative analysis; neoplasm metastasis; transforming growth factor beta1; autocrine effect; cancer relapse; base sequence; upregulation; osteoclast; osteoclasts; matrigel; dna primers; monocyte; osteoblast; connective tissue growth factor; bone cancer; dna, complementary; coculture; parathyroid hormone type 1 receptor; parathyroid hormone receptor 1; parathyroid hormone related protein; receptor, parathyroid hormone, type 1 |
| Journal Title: | International Journal of Cancer |
| Volume: | 121 |
| Issue: | 5 |
| ISSN: | 0020-7136 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2007-09-01 |
| Start Page: | 943 |
| End Page: | 954 |
| Language: | English |
| DOI: | 10.1002/ijc.22749 |
| PUBMED: | 17410535 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 15" - "Export Date: 17 November 2011" - "CODEN: IJCNA" - "Source: Scopus" |
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