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三叶草王

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Desjobert et al. showed that the expression of miR-29a was regulated by methylation and suggested the existence of a positive feedback loop involving DNMT3b [17]. Our data extend these observations and show that miR-29b expression is upregulated in response to treatment with a demethylating agent, which supports
the presence of a positive feedback loop in NSCLC cells. However, a similar regulation of expression by methylation was not observed for miR-29c. This could be attributed to the fact that miR-29c and miR-29b2 is expressed from a different locus (Chr 1q32.2) and the regulation pattern may be different from that of miR-29a
and miR-29b1 on chromosome 7. In addition, a different positive feedback loop regulating the expression of miR-29s via c-Myc has been proposed. The effect of the c-Myc oncogene on the repression of mir-29 promoter activity has been shown previously [16,31]. Furthermore, this occurs downstream of the Wnt pathway and could be activated byb-catenin. Therefore, miR-29s may indirectly suppress the transcription of c-Myc by modulating the Wnt/ b-catenin signaling pathway.
    In summary, we showed that DNMT3A and DNMT3B are involved in the down-regulation of WIF-1 expression and that miR-29s restore WIF-1 expression by suppressing DNMT3A and DNMT3B. Enforced expression of these miRNAs in lung cancer cells blocks Wnt/b-catenin signaling and inhibits tumor growth. In
addition, the expression of miR-29a and miR-29b may be partly regulated by DNMT3A and DNMT3B in a positive feedback loop. Our study provides new insights into the involvement of miRNAs in the Wnt pathway and underscores the fundamental role of these miRNAs as tumor suppressor genes.
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三叶草王: 金币+20, 翻译EPI+1, ★★★★★最佳答案 2014-08-26 15:00:53
Desjobert等(研究)表明,miR-29a的表达受甲基化调节,并指出(提示)有一由DNMT3b参与的正反馈环路存在[17]。我们的结果进一步拓展了这些(已经报告了的)观察结果,而且显示用去甲基化试剂处理可以引起miR-29b的向上调节,这(一发现)支持在NSCLC细胞中存在一正反馈环路。然而,并未观察到甲基化对miR-29c的表达有类似调节作用。这可能是由于miR-29c和miR-29b2是在不同位点上(1号染色体q32.2)表达的,其(表达)调节形式可能与位于7号染色体上的miR-29a和miR-29b1不同。此外,(有人)提出了调节miR-29s表达的另外一种由c-Myc参与的正反馈环路。以前的结果已经表明,c-Myc癌基因对miR-29启动子活性有抑制作用 [16,31]。而且,该作用发生于Wnt信号通路下游,并且可以被β-cateni激活。因此,miR-29s可能通过调节Wnt/β-catenin信号通路而间接抑制c-Myc的转录。

总之,我们(的结果)表明,DNMT3A和DNMT3B参与WIF-1表达的向下调节,而且miR-29s可以通过抑制DNMT3A和DNMT3B而恢复WIF-1的表达。让肺癌细胞强行表达这些miRNA(即miR-29s)可以阻断Wnt/β-catenin信号通路并抑制肿瘤生长。另外,在这一正反馈环路中,miR-29a和miR-29b的表达可能受DNMT3A和DNMT3B的部分调节。我们的研究对miRNA参与Wnt信号通路提供了新的见解,并强调了这些miRNA作为肿瘤抑制基因的基本作用。
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