MicroRNAs at the human 14q32 locus have prognostic significance in osteosarcoma
ABSTRACT BACKGROUND: Deregulation of microRNA (miRNA) transcript levels has been observed in many types of tumors including osteosarcoma. Molecular pathways regulated by differentially expressed miRNAs may contribute to the heterogeneous tumor behaviors observed in naturally occurring cancers. Thus, tumor-associated miRNA expression may provide informative biomarkers for disease outcome and metastatic potential in osteosarcoma patients. We showed previously that clusters of miRNAs at the 14q32 locus are downregulated in human osteosarcoma. METHODS: Human and canine osteosarcoma patient's samples with clinical follow-up data were used in this study. We used bioinformatics and comparative genomics approaches to identify miRNA based prognostic biomarkers in osteosarcoma. Kaplan-Meier survival curves and Whitney Mann U tests were conducted for validating the statistical significance. RESULTS: Here we show that an inverse correlation exists between aggressive tumor behavior (increased metastatic potential and accelerated time to death) and the residual expression of 14q32 miRNAs (using miR-382 as a representative of 14q32 miRNAs) in a series of clinically annotated samples from human osteosarcoma patients. We also show a comparable decrease in expression of orthologous 14q32 miRNAs in canine osteosarcoma samples, with conservation of the inverse correlation between aggressive behavior and expression of orthologous miRNA miR-134 and miR-544. CONCLUSIONS: We conclude that downregulation of 14q32 miRNA expression is an evolutionarily conserved mechanism that contributes to the biological behavior of osteosarcoma, and that quantification of representative transcripts from this family, such as miR-382, miR-134, and miR-544, provide prognostic and predictive markers that can assist in the management of patients with this disease.
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ABSTRACT: Osteosarcoma is the most common bone tumor in children, adolescents, and young adults. In contrast to other childhood malignancies, no biomarkers have been consistently identified as predictors of outcome. This study was conducted to assess the microRNAs(miRs) expression signatures in pre-treatment osteosarcoma specimens and correlate with outcome to identify biomarkers for disease relapse. A 42-miRs signature whose expression levels were associated with overall and relapse-free survival waas identified. There were 8 common miRs between the two sets of survival-associated miRs. Bioinformatic analyses of these survival-associated miRs suggested that they might regulate genes involved in ubiquitin proteasome system, TGFb, IGF, PTEN/AKT/mTOR, MAPK, PDGFR/RAF/MEK/ERK, and ErbB/HER pathways. The cohort consisted of 27 patients of 70% Mexican-American ethnicity. High-throughput RT-qPCR approach was used to generate quantitative expression of 754 miRs in the human genome. We examined tumor recurrence status, survival time and their association with miR expression levels by Cox proportional hazard regression analysis. TargetScan was used to predict miR/genes interactions, and functional analyses using KEGG, BioCarta, Gene Ontology were applied to these potential targets to predict deregulated pathways. Our findings suggested that these miRs might be potentially useful as prognostic biomarkers and therapeutic targets in pediatric osteosarcoma.
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ABSTRACT: The bone is a complex connective tissue composed of many different cell types such as osteoblasts, osteoclasts, chondrocytes, mesenchymal stem/progenitor cells, hematopoietic cells and endothelial cells, among others. The interaction between them is finely balanced through the processes of bone formation and bone remodeling, which regulates the production and biological activity of many soluble factors and extracellular matrix components needed to maintain the bone homeostasis in terms of cell proliferation, differentiation and apoptosis. Osteosarcoma (OS) emerges in this complex environment as a result of poorly defined oncogenic events arising in osteogenic lineage precursors. Increasing evidence supports that similar to normal development, the bone microenvironment (BME) underlies OS initiation and progression. Here, we recapitulate the physiological processes that regulate bone homeostasis and review the current knowledge about how OS cells and BME communicate and interact, describing how these interactions affect OS cell growth, metastasis, cancer stem cell fate and therapy outcome.Cellular and Molecular Life Sciences CMLS 05/2015; DOI:10.1007/s00018-015-1918-y · 5.86 Impact Factor
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ABSTRACT: We conducted a meta-analysis to comprehensively evaluate the correlations of ezrin expression with pathological characteristics and the prognosis of osteosarcoma. The MEDLINE (1966-2013), the Cochrane Library Database, EMBASE, CINAHL, Web of Science (1945-2013), and the Chinese Biomedical Database were searched without language restrictions. Meta-analyses conducted using STATA software were calculated. Ten studies met the inclusion criteria, including 459 patients with osteosarcoma. Meta-analysis results illustrated that ezrin expression may be closely associated with the recurrence of osteosarcoma or metastasis in osteosarcoma. Our findings also demonstrated that patients with grade III-IV osteosarcoma showed a higher frequency of ezrin expression than those with histological grade I-II osteosarcoma. Furthermore, we found that patients with positive expression of ezrin exhibited a shorter overall survival than those with negative ezrin expression. The results also indicated that positive ezrin expression was strongly correlated with poorer metastasis-free survival. Nevertheless, no significant relationships were observed between ezrin expression and clinical variables (age and gender). In the current meta-analysis, our results illustrated significant relationships of ezrin expression with pathological characteristics and prognosis of osteosarcoma. Thus, ezrin expression could be a promising marker in predicting the clinical outcome of patients with osteosarcoma.11/2014; 2014:837543. DOI:10.1155/2014/837543