Abstract
BackgroundTo investigate associations between WW domain-containing oxidoreductase (WWOX), runt-related transcription factor 2 (RUNX2) and vascular endothelial growth factor alpha (VEGFA) in human osteosarcoma (OS).MethodsCopy number aberrations of WWOX, RUNX2and VEGFA genes were detected by microarray comparative genomic hybridization (aCGH) in 10 fresh OS tissue samples. VEGFA gene alterations were also investigated and validated by fluorescence in situ hybridization (FISH) in 54 formalin-fixed and paraffin-embedded (FFPE) OS samples. Protein expression of WWOX, RUNX2 and VEGFA were examined in 54 FFPE OS samples by immunohistochemistry (IHC).ResultsAnalysis of previously published OS aCGH data (GSE9654) and aCGH data from this study (GSE19180) identified significant deletion of WWOX in 30% (6/20) of OS samples, whilst significant increase in both RUNX2 and VEGFA gene copy numbers were detected in 55% (11/20) and 60% (12/20) of OS samples, respectively. FISH demonstrated increased VEGFA gene copy number in 65.9% (31/47) of evaluable samples, in either focal or large fragment forms. Compared with positive expression of WWOX in 38.9% of the OS samples, positive expression of RUNX2 and VEGFA protein was found in 48.1 and 75.9% of samples. Although there was no significant association between gene copy number aberration and protein expression for WWOX and RUNX2, significant positive correlation between increased VEGFA gene copy number and VEGFA protein expression was observed. Although there was no significant reverse association between WWOX and RUNX2 expression, a significantly positive relationship was observed between RUNX2 and VEGFA protein expression.ConclusionsOur data show increased RUNX2 and VEGFA gene copy numbers and elevation of their respective proteins in human OS. Positive correlation of RUNX2 and VEGFA suggests that both increased VEGFA gene copy number and RUNX2 overexpression facilitate increased expression of VEGFA.
Highlights
To investigate associations between WW domain-containing oxidoreductase (WWOX), runt-related transcription factor 2 (RUNX2) and vascular endothelial growth factor alpha (VEGFA) in human osteosarcoma (OS)
No statistically significant association was found between WWOX expression and clinical pathologic factors, including sex, age, pTNM stage, recurrence, metastasis and survival, we found increased RUNX2 and VEGFA expression was significantly associated with age (P = 0.027) and sex(P = 0.012), respectively (Table 1)
The present study found no significant correlation between WWOX, RUNX2, and VEGFA genes with respect to gene copy number aberration
Summary
To investigate associations between WW domain-containing oxidoreductase (WWOX), runt-related transcription factor 2 (RUNX2) and vascular endothelial growth factor alpha (VEGFA) in human osteosarcoma (OS). OS frequently occurs in the metaphysis of actively growing long bones and is characteristic of short and rapid progression. It has high incidence of pulmonary metastasis and poor prognosis, and mainly affects children and adolescents [1]. RUNX2 is a critical element for VEGF mRNA transcription and protein expression in tumorigenesis [22]. We observed WWOX, RUNX2 and VEGFA gene copy number status and protein expression levels using microarray comparative genomic hybridization (aCGH), immunohistochemistry (IHC) staining and fluorescence in situ hybridization (FISH), in order to investigate correlations between these components
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