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三叶草王铁虫 (正式写手)
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Concurrent aberrant activation of the Wnt pathway and downregulation of Wnt antagonists are common in cancer cells. Silencing or downregulation of the WIF-1 gene by promoter hypermethylation has been detected in several malignancies including lung cancer, and it has been associated with tumorigenesis. In the present study, three DNMTs (DNMT1, DNMT3A and DNMT3B) were found to be up-regulated in NSCLC tumor tissues and their suppression restored the expression of WIF-1 in NSCLC cells. Because DNMT3A and DNMT3B are negatively regulated by miR-29s, we explored the involvement of the miR-29 family in the aberrant regulation of Wnt signaling. Mir-29 family members have been described as tumor suppressor genes and their expression is down-regulated in several cancers, including NSCLC,cholangiocarcinoma[27]and acute myeloid leukemia[28]. We observed that the expression of miR-29s was positively correlated with the expression of WIF-1 in NSCLC tissue. The results of MSP and Western blotting indicated that miR-29s contribute to the reduction of promoter methylation of the WIF-1 gene and positively regulate the expression of WIF-1. These results confirmed our hypothesis and link miR-29s to the Wnt pathway. In the present study, we showed that miR-29s inhibited Wnt/bcatenin signaling as shown by the effect of overexpression of miR-29 family members on the downregulation ofb-catenin expression. In agreement with previous studies [14,29,30], we also showed that miR-29s inhibit cell proliferation and induce apoptosis in NSCLC cells. A previous study showed that miR-29s sensitize tumor cell to apoptosis by targeting Mcl-1 or the p53 pathway.Our results showed that WIF-1 knockdown abolishes these effects of miR-29s, suggesting that inhibition of Wnt signaling could be another potential mechanism mediating the anti-tumor effects of miR-29s. |
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至尊木虫 (知名作家)
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- 翻译EPI: 1690
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- 专业: 肿瘤发生
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RXMCDM: 金币+1, 多谢应助！ 2014-08-27 10:22:25
三叶草王: 金币+20, 翻译EPI+1, ★★★★★最佳答案 2014-08-27 15:52:11
RXMCDM: 金币+1, 多谢应助！ 2014-08-27 10:22:25
三叶草王: 金币+20, 翻译EPI+1, ★★★★★最佳答案 2014-08-27 15:52:11
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在癌症细胞中，同时出现Wnt信号通路的异常激活和Wnt拮抗剂的下调是（很）常见的。 在包括肺癌在内的几种恶性肿瘤中，发现可以通过启动子超甲基化而使WIF-1基因静默或下调，而且与肿瘤发生具有相关性。在本研究中，(我们)发现在NSCLC肿瘤组织中三种DNMTs（DNMT1、DNMT3A和DNMT3B）有向上调节，而且抑制它们表达后可以恢复WIF-1在NSCLC细胞中的表达。因为DNMT3A和DNMT3B受miR-29s的负调节，我们探讨了miR-29家族在Wnt信号通路异常调节中的参与情况。miR29家族成员被认为是肿瘤抑制基因，其表达在数种癌症中是向下调节的，包括NSCLC、胆管癌[27]和急性粒细胞性白血病[28]。我们观察到，miR-29s在NSCLC组织中与WIF-1的表达呈正相关。MSP结果和Western印迹表明，miR-29s可以引起WIF-1基因启动子甲基化降低并正向调节WIF-1的表达。这些结果证实了我们的假说并将miR-29s与Wnt信号通路联系起来。在本研究中，我们表明，miR-29s可以抑制Wnt/β-catenin信号通路，体现在miR-29家族成员过度表达对β-catenin表达的向下调节作用。与以前的研究一致 [14,29,30]，我们也发现miR-29s在NSCLC细胞中可以抑制细胞增殖并诱导其凋亡。曾有一研究表明，miR-29s可以通过靶向Mcl-1或p53通路而使肿瘤细胞更易于发生凋亡。我们的结果表明敲减WIF-1可以消除miR-29s的这些作用，提示抑制Wnt信号通路可能是介导miR-29s抗肿瘤作用的另一可能（潜在）机制。 |
2楼2014-08-27 09:02:15
