Department of Biomedicine, Aarhus University, Denmark.
Laboratory for Epigenetics and Environment, Centre National de la Recherche en Génomique Humaine, CEA - Institut de Biologie Francois Jaçob, Evry, France.
Mol Oncol. 2018 Jan;12(1):114-131. doi: 10.1002/1878-0261.12154. Epub 2017 Dec 1.
Osteosarcoma (OS) is an aggressive bone tumor primarily affecting children and adolescents. The etiology of OS is not fully understood. Thus, there is a great need to obtain a better understanding of OS development and progression. Alterations in miRNA expression contribute to the required molecular alterations for neoplastic initiation and progression. This study is the first to investigate miRNA expression in OS in a large discovery and validation cohort comprising a total of 101 OS samples. We established the signature of altered miRNA expression in OS by profiling the expression level of 752 miRNAs in 23 OS samples using sensitive LNA-enhanced qPCR assays. The identified miRNA expression changes were correlated with gene expression in the same samples. Furthermore, miRNA expression changes were validated in a second independent cohort consisting of 78 OS samples. Analysis of 752 miRNAs in the discovery cohort led to the identification of 33 deregulated miRNAs in OS. Twenty-nine miRNAs were validated with statistical significance in the second cohort comprising 78 OS samples. miRNA/mRNA targets were determined, and 361 genes with an inverse expression of the target miRNA were identified. Both the miRNAs and the identified target genes were associated with multiple pathways related to cancer as well as bone cell biology, thereby correlating the deregulated miRNAs with OS tumorigenesis. An analysis of the prognostic value of the 29 miRNAs identified miR-221/miR-222 to be significantly associated with time to metastasis in both cohorts. This study contributes to a more profound understanding of OS tumorigenesis, by substantiating the importance of miRNA deregulation. We have identified and validated 29 deregulated miRNAs in the - to our knowledge - largest discovery and validation cohorts used so far for miRNA analyses in OS. Two of the miRNAs showed a promising potential as prognostic biomarkers for the aggressiveness of OS.
骨肉瘤（OS）是一种主要影响儿童和青少年的侵袭性骨肿瘤。OS 的病因尚不完全清楚。因此，需要更好地了解 OS 的发展和进展。miRNA 表达的改变有助于肿瘤起始和进展所需的分子改变。本研究首次在包括总共 101 个 OS 样本的大型发现和验证队列中研究了 OS 中的 miRNA 表达。我们通过使用敏感的 LNA 增强 qPCR 分析在 23 个 OS 样本中分析了 752 个 miRNA 的表达水平，从而确定了 OS 中 miRNA 表达的特征。鉴定的 miRNA 表达变化与相同样本中的基因表达相关。此外，在由 78 个 OS 样本组成的第二个独立队列中验证了 miRNA 表达变化。在发现队列中对 752 个 miRNA 的分析导致在 OS 中鉴定出 33 个失调的 miRNA。在包含 78 个 OS 样本的第二个队列中，有 29 个 miRNA 具有统计学意义得到验证。确定了 miRNA/mRNA 靶标，并鉴定了 361 个靶 miRNA 表达相反的基因。失调的 miRNA 与 OS 肿瘤发生相关，这与癌症以及骨细胞生物学的多个途径相关，从而将失调的 miRNA 与 OS 肿瘤发生相关联。对 29 个 miRNA 的预后价值分析表明，miR-221/miR-222 在两个队列中均与转移时间显着相关。本研究通过证实 miRNA 失调的重要性，对 OS 肿瘤发生有了更深入的了解。我们已经在迄今为止用于 OS 中 miRNA 分析的最大发现和验证队列中鉴定和验证了 29 个失调的 miRNA。其中两个 miRNA 作为 OS 侵袭性的预后生物标志物具有很大的潜力。
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