Prognostic value of CCN3 in osteosarcoma.
OBJECTIVE
Osteosarcoma, the most common bone tumor, lacks prognostic markers that could distinguish patients before therapy and drive treatment choices. We assessed the prognostic value of CCN1, CCN2, and CCN3 genes, involved in fundamental biological processes.


METHODS
Expression of CCN1, CCN2, and CCN3 was measured by quantitative PCR in 45 newly diagnosed osteosarcomas. Cancer-specific survival was estimated using the Kaplan-Meier method. Associations with osteoblastic differentiation and/or drug response genes were assessed in tumor cells using Spearman correlation and Fisher's exact tests.


RESULTS
CCN1 and CCN2 expression was associated with genes involved in commitment of mesenchymal stem cells toward osteoblasts and in early phases of osteoblastic differentiation (RUNX family genes; cadherin 4, 11, and 13; jun and fos; collagen I and SPARC). Although CCN3 is barely expressed in normal proliferating osteoblasts and mesenchymal stem cells, its expression was generally high in osteosarcoma and its level of expression did not correlate with any specific osteoblastic differentiation genes. High expression of CCN3 significantly correlated with worse prognosis in osteosarcoma. This may be only partly explained by the association with the expression of multidrug resistance-related protein 1 and 4, two ATP-binding cassette transporters that also acted as predictors of worse outcome in our study.


CONCLUSIONS
Our study showed temporal and coordinated expression of CCN1, CCN2, and CCN3 genes during osteoblastic differentiation and highlighted significant differences between human normal and osteosarcoma cell differentiation in vitro. CCN1 and CCN2 expression shows no prognostic relevance in osteosarcoma. In contrast, assessment for CCN3 expression levels at diagnosis may represent a useful molecular tool to early identification of patients with different prognosis.
Perbal
Bernard
B
Laboratorio di Ricerca Oncologica and Laboratorio di Rigenerazione Tissutale Ossea, Istituti Ortopedici Rizzoli, Bologna, Italy.
Zuntini
Monia
M
Zambelli
Diana
D
Serra
Massimo
M
Sciandra
Marika
M
Cantiani
Lara
L
Lucarelli
Enrico
E
Picci
Piero
P
Scotlandi
Katia
K
D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D055513:Connective Tissue Growth Factor; D055515:Cysteine-Rich Protein 61; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008648:Mesoderm / Q000473:pathology; D055514:Nephroblastoma Overexpressed Protein; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000473:pathology
C501848:CCN1 protein, human; C526317:CCN2 protein, human; C526319:CCN3 protein, human; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055514:Nephroblastoma Overexpressed Protein; D055513:Connective Tissue Growth Factor