The Pro-Apoptotic Role of the Regulatory Feedback Loop between miR-124 and PKM1/HNF4α in Colorectal Cancer Cells
The Pro-Apoptotic Role of the Regulatory Feedback Loop between miR-124 and PKM1/HNF4α in Colorectal Cancer Cells
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结直肠癌细胞中 miR-124 和 PKM1/HNF4α 之间的调节反馈环路的促凋亡作用。
DOI：
10.3390/ijms15034318
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发表时间：
2014-03-01
影响因子：
5.6
通讯作者：
Hu, Yu
中科院分区：
文献类型：
--
作者：
Sun, Yan;Zhao, Xiaoping;Hu, Yu
越来越多的证据表明，miRNA调节电路在肿瘤的发生发展中起着重要作用。我们先前报道，miR-124与结直肠癌的预后相关，这是由于PKM依赖的糖酵解调节。然而，miR-124调控结直肠癌细胞凋亡的机制在很大程度上仍不清楚。在这里，我们显示了miR-124诱导了一组结直肠癌细胞株的显著凋亡。MiR-124激活线粒体凋亡通路。此外，miR-124的促凋亡作用依赖于PKM1/2水平的状态。在miR-124诱导的细胞凋亡中，需要PKM1。PKM1通过直接的蛋白质-蛋白质相互作用促进HNF4与miR-124启动子区域的结合并转录miR-124。此外，在miR-124存在的情况下，HNF4或PKM1对结直肠癌细胞的凋亡有更显著的影响。然而，抑制miR-124可阻断HNF4或PKM1诱导的细胞凋亡。这些数据表明，miR-124不仅改变了与糖代谢有关的基因的表达，而且还刺激了癌细胞的凋亡。此外，miR-124与PKM1/HNF4之间的正反馈环在结直肠癌细胞的凋亡中起重要作用，提示干扰这一调节回路可能成为结直肠癌治疗的一种潜在的治疗手段。
Accumulating evidence indicates that miRNA regulatory circuits play important roles in tumorigenesis. We previously reported that miR-124 is correlated with prognosis of colorectal cancer due to PKM-dependent regulation of glycolysis. However, the mechanism by which miR-124 regulates apoptosis in colorectal cancer remains largely elusive. Here, we show that miR-124 induced significant apoptosis in a panel of colorectal cancer cell lines. The mitochondrial apoptosis pathway was activated by miR-124. Furthermore, the pro-apoptotic role of miR-124 was dependent on the status of PKM1/2 level. PKM1 was required for miR-124-induced apoptosis. Via direct protein-protein interaction, PKM1 promoted HNF4 binding to the promoter region of miR-124 and transcribing miR-124. Moreover, HNF4 or PKM1 had a more dramatic effect on colorectal cancer cell apoptosis in the presence of miR-124. However, inhibition of miR-124 blocked cell apoptosis induced by HNF4 or PKM1. These data indicate that miR-124 not only alters the expression of genes involved in glucose metabolism but also stimulates cancer cell apoptosis. In addition, the positive feedback loop between miR-124 and PKM1/HNF4 plays an important role in colorectal cancer cell apoptosis; it suggests that disrupting this regulatory circuit might be a potential therapeutic tool for colorectal cancer treatment.