A systematic screen for micro-RNAs regulating the canonical Wnt pathway.
A systematic screen for micro-RNAs regulating the canonical Wnt pathway.
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DOI：
10.1371/journal.pone.0026257
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Dasgupta R
中科院分区：
文献类型：
--
作者：
Anton R;Chatterjee SS;Simundza J;Cowin P;Dasgupta R
已知MicroRNAs （miRs）和典型Wnt通路在人类癌症中失调，并在癌症的发生和发展中发挥关键作用。为了鉴定可以调节Wnt通路活性的miRs，我们在人HEK293细胞中进行了基于细胞的470个miRs过表达筛选。我们确定了38个激活或抑制典型Wnt通路的候选mir。对所有已验证的候选miRs的文献调查显示，抑制wnt的miRs往往是抗肿瘤的miRs，在癌症中下调，而激活wnt的miRs往往是肿瘤的miRs，在肿瘤发生期间上调。对三种候选miR-1、miR-25和miR-613的上位性功能验证证实了它们在抑制Wnt通路中的抑制作用，并表明miR-25可能在<s:2> -catenin （β-cat）水平上起作用，miR-1和miR-613在β-cat上游起作用。miR-25和miR-1在选择表现出Wnt信号失调的人结肠癌细胞系过程中抑制细胞增殖和活力。最后，将表达miR-1的慢病毒转导到来自传导蛋白- lacz小鼠的原代乳腺类器官中，显著降低了wnt敏感β-gal报告基因的表达。总之，这些发现提示wnt调节miRs作为wnt依赖性疾病（如癌症）的诊断和治疗工具的潜在用途。
MicroRNAs (miRs) and the canonical Wnt pathway are known to be dysregulated in human cancers and play key roles during cancer initiation and progression. To identify miRs that can modulate the activity of the Wnt pathway we performed a cell-based overexpression screen of 470 miRs in human HEK293 cells. We identified 38 candidate miRs that either activate or repress the canonical Wnt pathway. A literature survey of all verified candidate miRs revealed that the Wnt-repressing miRs tend to be anti-oncomiRs and down-regulated in cancers while Wnt-activating miRs tend to be oncomiRs and upregulated during tumorigenesis. Epistasis-based functional validation of three candidate miRs, miR-1, miR-25 and miR-613, confirmed their inhibitory role in repressing the Wnt pathway and suggest that while miR-25 may function at the level of â-catenin (β-cat), miR-1 and miR-613 act upstream of β-cat. Both miR-25 and miR-1 inhibit cell proliferation and viability during selection of human colon cancer cell lines that exhibit dysregulated Wnt signaling. Finally, transduction of miR-1 expressing lentiviruses into primary mammary organoids derived from Conductin-lacZ mice significantly reduced the expression of the Wnt-sensitive β-gal reporter. In summary, these findings suggest the potential use of Wnt-modulating miRs as diagnostic and therapeutic tools in Wnt-dependent diseases, such as cancer.
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4.7
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