Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Orphanet J Rare Dis. 2013 Jan 11;8:7. doi: 10.1186/1750-1172-8-7.
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.
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.
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.
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.
微 RNA（miRNA）转录水平的失调在包括骨肉瘤在内的许多类型的肿瘤中都有观察到。受差异表达 miRNA 调控的分子通路可能有助于解释自然发生的癌症中观察到的肿瘤异质性行为。因此，肿瘤相关 miRNA 的表达可能为骨肉瘤患者的疾病结局和转移潜能提供有信息价值的生物标志物。我们之前已经表明，14q32 基因座上的 miRNA 簇在人骨肉瘤中下调。
本研究使用具有临床随访数据的人骨肉瘤和犬骨肉瘤患者样本。我们使用生物信息学和比较基因组学方法来鉴定骨肉瘤中的 miRNA 预后生物标志物。通过 Kaplan-Meier 生存曲线和 Whitney Mann U 检验来验证统计显著性。
在这里，我们显示在一系列具有临床注释的人骨肉瘤患者样本中，侵袭性肿瘤行为（增加转移潜能和加速死亡时间）与 14q32 miRNA 的残留表达之间存在负相关（使用 miR-382 作为 14q32 miRNAs 的代表）。我们还显示在犬骨肉瘤样本中，同源 14q32 miRNAs 的表达也有类似的降低，并且与同源 miRNA miR-134 和 miR-544 的表达之间存在侵袭性行为的负相关。
我们得出结论，14q32 miRNA 表达的下调是一种进化保守的机制，有助于骨肉瘤的生物学行为，并且对该家族的代表性转录物（如 miR-382、miR-134 和 miR-544）进行定量分析，提供了可以协助管理这种疾病患者的预后和预测标志物。
