Profiling and functional analyses of microRNAs and their target gene products in human uterine leiomyomas.
Profiling and functional analyses of microRNAs and their target gene products in human uterine leiomyomas.
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人子宫平滑肌瘤中 MicroRNA 及其靶基因产物的谱分析和功能分析
DOI：
10.1371/journal.pone.0012362
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发表时间：
2010-08-24
期刊：
影响因子：
3.7
通讯作者：
Wei JJ
中科院分区：
文献类型：
--
作者：
Zavadil J;Ye H;Liu Z;Wu J;Lee P;Hernando E;Soteropoulos P;Toruner GA;Wei JJ
背景人类子宫平滑肌瘤（乌尔姆）的特征是大量基因和非编码调节microRNA的失调。为了确定microRNA：：mRNA与乌尔姆发病机制的相关性，我们研究了改变的microRNA表达与ULM和匹配的子宫肌层中预测的靶基因之间的总体相关性模式。方法学/主要发现ULM中microRNA与mRNA表达的负相关模式揭示了多种候选途径的参与，包括广泛的转录重编程，细胞增殖控制，MAP激酶，TGF-β，WNT，JAK/STAT信号传导，细胞粘附重塑，以及细胞-细胞和细胞-基质接触。我们进一步研究了36对子宫肌瘤和匹配的子宫肌层中所选靶基因蛋白产物和microRNA表达之间的相关性。我们发现，许多失调的microRNA在蛋白质水平上与其靶点呈负相关。8例乌尔姆患者的比较基因组杂交（CGH）显示，两个不同染色体区域的部分共享缺失可能是癌症相关microRNA表达缺失的原因，因此可能通过靶mRNA的失调促进乌尔姆发病机制。最后，我们在体外功能上测试了选定的癌症相关microRNA对其预测的靶基因的阻遏作用。结论/意义我们发现，一些但不是所有的预测和负相关的靶基因在ULMs可以直接调控的microRNA在体外。我们的研究结果提供了一个广泛的概述，潜在的子宫ULM肿瘤发生的分子事件，并确定选择的遗传和调节事件，改变microRNA的表达，并可能发挥重要作用，在乌尔姆病理生物学积极调节肿瘤生长，同时保持非侵入性的特点ULM。
Background Human uterine leiomyomas (ULM) are characterized by dysregulation of a large number of genes and non-coding regulatory microRNAs. In order to identify microRNA::mRNA associations relevant to ULM pathogenesis, we examined global correlation patterns between the altered microRNA expression and the predicted target genes in ULMs and matched myometria. Methodology/Principal Findings Patterns of inverse association of microRNA with mRNA expression in ULMs revealed an involvement of multiple candidate pathways, including extensive transcriptional reprogramming, cell proliferation control, MAP kinase, TGF-β, WNT, JAK/STAT signaling, remodeling of cell adhesion, and cell-cell and cell-matrix contacts. We further examined the correlation between the expression of the selected target gene protein products and microRNAs in thirty-six paired sets of leiomyomas and matched myometria. We found that a number of dysregulated microRNAs were inversely correlated with their targets at the protein level. The comparative genomic hybridization (CGH) in eight ULM patients revealed that partially shared deletions of two distinct chromosomal regions might be responsible for loss of cancer–associated microRNA expression and could thus contribute to the ULM pathogenesis via deregulation of target mRNAs. Last, we functionally tested the repressor effects of selected cancer-related microRNAs on their predicted target genes in vitro. Conclusions/Significance We found that some but not all of the predicted and inversely correlated target genes in ULMs can be directly regulated by microRNAs in vitro. Our findings provide a broad overview of molecular events underlying the tumorigenesis of uterine ULMs and identify select genetic and regulatory events that alter microRNA expression and may play important roles in ULM pathobiology by positively regulating tumor growth while maintaining the non-invasive character of ULMs.
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