The EuroBoNet Network of Excellence on Bone Tumours, Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
PLoS One. 2012;7(10):e48086. doi: 10.1371/journal.pone.0048086. Epub 2012 Oct 25.
Osteosarcomas are the most common primary malignant tumors of bone and show multiple and complex genomic aberrations. miRNAs are non-coding RNAs capable of regulating gene expression at the post transcriptional level, and miRNAs and their target genes may represent novel therapeutic targets or biomarkers for osteosarcoma. In order to investigate the involvement of miRNAs in osteosarcoma development, global microarray analyses of a panel of 19 human osteosarcoma cell lines was performed.
We identified 177 miRNAs that were differentially expressed in osteosarcoma cell lines relative to normal bone. Among these, miR-126/miR-126*, miR-142-3p, miR-150, miR-223, miR-486-5p and members of the miR-1/miR-133a, miR-144/miR-451, miR-195/miR-497 and miR-206/miR-133b clusters were found to be downregulated in osteosarcoma cell lines. All miRNAs in the paralogous clusters miR-17-92, miR-106b-25 and miR-106a-92 were overexpressed. Furthermore, the upregulated miRNAs included miR-9/miR-9*, miR-21*, miR-31/miR-31*, miR-196a/miR-196b, miR-374a and members of the miR-29 and miR-130/301 families. The most interesting inversely correlated miRNA/mRNA pairs in osteosarcoma cell lines included miR-9/TGFBR2 and miR-29/p85α regulatory subunit of PI3K. PTEN mRNA correlated inversely with miR-92a and members of the miR-17 and miR-130/301 families. Expression profiles of selected miRNAs were confirmed in clinical samples. A set of miRNAs, miR-1, miR-18a, miR-18b, miR-19b, miR-31, miR-126, miR-142-3p, miR-133b, miR-144, miR-195, miR-223, miR-451 and miR-497 was identified with an intermediate expression level in osteosarcoma clinical samples compared to osteoblasts and bone, which may reflect the differentiation level of osteosarcoma relative to the undifferentiated osteoblast and fully differentiated normal bone.
This study provides an integrated analysis of miRNA and mRNA in osteosarcoma, and gives new insight into the complex genetic mechanisms of osteosarcoma development and progression.
骨肉瘤是最常见的原发性骨恶性肿瘤，表现出多种复杂的基因组异常。miRNAs 是一种能够在转录后水平调节基因表达的非编码 RNA，miRNAs 及其靶基因可能代表骨肉瘤的新的治疗靶点或生物标志物。为了研究 miRNAs 参与骨肉瘤发生的机制，我们对一组 19 个人骨肉瘤细胞系进行了全基因组微阵列分析。
与正常骨相比，我们在骨肉瘤细胞系中发现了 177 个差异表达的 miRNAs。其中，miR-126/miR-126*、miR-142-3p、miR-150、miR-223、miR-486-5p 和 miR-1/miR-133a、miR-144/miR-451、miR-195/miR-497 和 miR-206/miR-133b 簇中的成员表达下调。miR-17-92、miR-106b-25 和 miR-106a-92 这三个 miRNA 家族中的所有 miRNA 都过表达。此外，上调的 miRNA 包括 miR-9/miR-9*、miR-21*、miR-31/miR-31*、miR-196a/miR-196b、miR-374a 和 miR-29 和 miR-130/301 家族的成员。骨肉瘤细胞系中最有趣的反向相关 miRNA/mRNA 对包括 miR-9/TGFBR2 和 miR-29/p85α 调节亚基的 PI3K。PTEN mRNA 与 miR-92a 和 miR-17 和 miR-130/301 家族的成员呈负相关。在临床样本中验证了所选 miRNA 的表达谱。一组 miRNA，miR-1、miR-18a、miR-18b、miR-19b、miR-31、miR-126、miR-142-3p、miR-133b、miR-144、miR-195、miR-223、miR-451 和 miR-497 在骨肉瘤临床样本中的表达水平介于成骨细胞和骨之间，与成骨细胞和完全分化的正常骨相比，这可能反映了骨肉瘤相对于未分化的成骨细胞和完全分化的正常骨的分化水平。
本研究对骨肉瘤中的 miRNA 和 mRNA 进行了综合分析，为骨肉瘤发生和发展的复杂遗传机制提供了新的见解。
