miR-301a as an NF-κB activator in pancreatic cancer cells
miR-301a as an NF-κB activator in pancreatic cancer cells
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DOI：
10.1038/emboj.2010.296
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发表时间：
2011-01-05
期刊：
影响因子：
11.4
通讯作者：
Li, Yong
中科院分区：
文献类型：
--
作者：
Lu, Zhongxin;Li, Yan;Li, Yong
核因子-kappaB在大多数人胰腺癌中被结构性激活，这是一种致命的恶性肿瘤，5年生存率约为5%。在这项工作中，我们研究了microRNAs(MiRNAs)是否有助于胰腺癌中核因子-kappaB的激活。我们证明miR-301a下调核因子-kappaB抑制因子(Nkrf)并上调核因子-kappaB的活性。由于核因子-kappa B促进miR-301a的转录，我们的结果支持一个正反馈环作为持续的核因子-kappa B激活的机制，其中miR-301a抑制Nkrf以提高核因子-kappa B的活性，从而促进miR-301a的转录。人胰腺癌组织中Nkrf表达下调，miR-301a表达上调。此外，在胰腺癌细胞中抑制miR-301a或上调Nkrf可导致核因子-kappa B靶基因表达降低，从而抑制移植瘤的生长，提示miR-301a过表达有助于核因子-kappaB的激活。揭示这种由miRNA激活核因子-kappaB的新机制为胰腺癌的治疗干预提供了新的途径。EMBO期刊(2011)30，57-67。DOI：10.1038/Intemj.2010.296；2010年11月26日在线发布
NF-kappa B is constitutively activated in most human pancreatic adenocarcinoma, which is a deadly malignancy with a 5-year survival rate of about 5%. In this work, we investigate whether microRNAs (miRNAs) contribute to NF-kappa B activation in pancreatic cancer. We demonstrate that miR-301a down-regulates NF-kappa B-repressing factor (Nkrf) and elevates NF-kappa B activation. As NF-kappa B promotes the transcription of miR-301a, our results support a positive feedback loop as a mechanism for persistent NF-kappa B activation, in which miR-301a represses Nkrf to elevate NF-kappa B activity, which in turn promotes miR-301a transcription. Nkrf was found down-regulated and miR-301a up-regulated in human pancreatic adenocarcinoma tissues. Moreover, miR-301a inhibition or Nkrf up-regulation in pancreatic cancer cells led to reduced NF-kappa B target gene expression and attenuated xenograft tumour growth, indicating that miR-301a overexpression contributes to NF-kappa B activation. Revealing this novel mechanism of NF-kappa B activation by an miRNA offers new avenues for therapeutic interventions against pancreatic cancer. The EMBO Journal (2011) 30, 57-67. doi:10.1038/emboj.2010.296; Published online 26 November 2010