miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect
miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect
复制标题
miR-124、miR-137 和 miR-340 通过抑制 Warburg 效应来调节结直肠癌的生长。
DOI：
10.3892/or.2012.1958
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发表时间：
2012-10-01
期刊：
影响因子：
4.2
通讯作者：
Hu, Yu
中科院分区：
文献类型：
--
作者：
Sun, Yan;Zhao, Xiaoping;Hu, Yu
结直肠癌是最具挑战性的疾病之一。越来越多的证据表明microRNAs（miRNAs）的异常表达与结直肠癌的发病机制有关。癌细胞重新编程代谢途径以维持更高的增殖率。miRNA在结直肠癌中的作用机制是否涉及代谢重编程以及miRNA改变癌症代谢的机制尚不清楚。在此，我们发现miR-124、miR-137和miR-340与结直肠癌的不良预后相关。这些miRNAs的表达抑制结直肠癌细胞的生长。PKM（丙酮酸激酶同工酶）选择性剪接蛋白（PTB 1/hnRNAPA 1/hnRNAPA 2）控制外显子9（PKM 1）或外显子10（PKM 2）的包含，是miR-124、miR-137和miR-340的靶向蛋白。因此，miR-124、miR-137和miR-340将PKM基因表达从PKM 2转换为PKM 1。高比例的PKM 1/PKM 2抑制糖酵解速率，但提高葡萄糖流入氧化磷酸化。这些结果表明，miRNA（miR-124，miR-137和miR-340）通过抵消由于调节PKM基因的选择性剪接引起的瓦尔堡效应而损害结直肠癌生长。
Colorectal cancer represents one of the most challenging diseases. Increasing evidence indicates that aberrant expression of microRNAs (miRNAs) is related to pathogenesis of colorectal cancer. Cancer cells reprogram metabolic pathways to sustain higher proliferation rates. Whether mechanisms underlying the role of miRNA in colorectal cancer are involved in metabolic reprogramming and the mechanisms through which miRNAs alter cancer metabolism are as yet unknown. Herein, we show that miR-124, miR-137 and miR-340 are associated with poor prognosis of colorectal cancer. Expression of these miRNAs inhibits the growth of colorectal cancer cells. PKM (pyruvate kinase isozyme) alternative splicing proteins (PTB1/hnRNAPA1/hnRNAPA2), which control the inclusion of exon 9 (PKM1) or exon 10 (PKM2), are targeted by miR-124, miR-137 and miR-340. Consequently, miR-124, miR-137 and miR-340 switch PKM gene expression from PKM2 to PKM1. High ratios of PKM1/PKM2 inhibit the glycolysis rate, but elevate the glucose flux into oxidative phosphorylation. These results demonstrate that miRNAs (miR-124, miR-137 and miR-340) impair colorectal cancer growth by counteracting the Warburg effect due to regulating alternative splicing of the PKM gene.