miRNA signatures associate with pathogenesis and progression of osteosarcoma.
miRNA signatures associate with pathogenesis and progression of osteosarcoma.
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DOI：
10.1158/0008-5472.can-11-2663
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发表时间：
2012-04-01
期刊：
影响因子：
11.2
通讯作者：
Aqeilan RI
中科院分区：
文献类型：
--
作者：
Jones KB;Salah Z;Del Mare S;Galasso M;Gaudio E;Nuovo GJ;Lovat F;LeBlanc K;Palatini J;Randall RL;Volinia S;Stein GS;Croce CM;Lian JB;Aqeilan RI
骨肉瘤仍然是青少年癌症死亡的主要原因。二十年来，治疗模式和存活率没有任何改善。由于缺乏治疗途径，骨肉瘤的分子病因学仍然难以捉摸。MicroRNAs(MiRNAs)对发育和癌症的细胞生物学有深远的影响。它们在骨肉瘤形成中的作用在很大程度上仍未被研究。在这里，我们首次从手术获取的人类患者样本中鉴定出反映骨肉瘤发病机制的miRNA签名。该特征包括miR-181a、miR-181b和miR-181c的高表达以及miR-16、miR-29b和miR-142-5p的低表达。我们还证明miR-181b和miR-29b在肿瘤组织中仅限于不同的细胞群表达。此外，治疗前活检样本中miR-27a和miR-181c*的高表达是发生临床转移疾病的患者的特征。此外，在治疗前样本中miR-451和miR-15b的高表达与随后的化疗阳性反应相关。在骨肉瘤细胞系的体外和体内功能验证证实了miR-16的肿瘤抑制作用和miR-27A的促转移作用。此外，实时定量聚合酶链式反应证实miR-16和miR-27A的预测靶基因表达下调。根据miR-16、miR142-5p、miR-29b、miR-181a/b和miR-27a的预测靶点，对骨肉瘤标本和对照的cDNA进行Affymetrix阵列分析。这项分析揭示了正负相关，突出了已知的对骨肉瘤重要的途径，以及新的基因。因此，我们的发现建立了与骨肉瘤发病机制相关的miRNA信号，以及关键的治疗前转移和治疗反应的生物标志物。
Osteosarcoma remains a leading cause of cancer death in adolescents. Treatment paradigms and survival rates have not improved in two decades. Driving the lack of therapeutic inroads, the molecular etiology of osteosarcoma remains elusive. MicroRNAs (miRNAs) have demonstrated far-reaching effects on the cellular biology of development and cancer. Their role in osteosarcomagenesis remains largely unexplored. Here we identify for the first time an miRNA signature reflecting the pathogenesis of osteosarcoma from surgically procured samples from human patients. The signature includes high expression of miR-181a, miR-181b, and miR-181c as well as reduced expression of miR-16, miR-29b, and miR-142-5p. We also demonstrate that miR-181b and miR-29b exhibit restricted expression to distinct cell populations in the tumor tissue. Further, higher expression of miR-27a and miR-181c* in pre-treatment biopsy samples characterized patients who developed clinical metastatic disease. In addition, higher expression of miR-451 and miR-15b in pre-treatment samples correlated with subsequent positive response to chemotherapy. In vitro and in vivo functional validation in osteosarcoma cell lines confirmed the tumor suppressive role of miR-16 and the pro-metastatic role of miR-27a. Furthermore, predicted target genes for miR-16 and miR-27a were confirmed as down-regulated by real-time PCR. Affymetrix array profiling of cDNAs from the osteosarcoma specimens and controls were interrogated according to predicted targets of miR-16, miR142-5p, miR-29b, miR-181a/b, and miR-27a. This analysis revealed positive and negative correlations highlighting pathways of known importance to osteosarcoma, as well as novel genes. Thus, our findings establish a miRNA signature associated with pathogenesis of osteosarcoma as well as critical pre-treatment biomarkers of metastasis and responsiveness to therapy.