miR-378☆ Mediates Metabolic Shift in Breast Cancer Cells via the PGC-1β/ERRγ Transcriptional Pathway
miR-378☆ Mediates Metabolic Shift in Breast Cancer Cells via the PGC-1β/ERRγ Transcriptional Pathway
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DOI：
10.1016/j.cmet.2010.09.002
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发表时间：
2010-10-06
期刊：
影响因子：
29
通讯作者：
Giguere, Vincent
中科院分区：
文献类型：
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作者：
Eichner, Lillian J.;Perry, Marie-Claude;Giguere, Vincent
癌细胞代谢的特点通常是从氧化途径转变为糖酵解生物能量途径，这种现象被称为华宝效应。MIR-378(STAR)嵌入PPARGC1b中，PPARGC1b编码PGC-1β，PGC-1β是氧化能量代谢的转录调节因子。在这里，我们表明miR-378(STAR)的表达受ERBB2的调节，并诱导乳腺癌细胞的代谢转变。MIR-378(STAR)通过抑制两个PGC-1β伙伴ERR伽马和GABPA的表达来实现这一功能，导致三羧酸循环基因表达和氧气消耗减少，乳酸产量和细胞增殖增加。原位杂交实验表明miR-378(STAR)的表达与乳腺癌的进展有关。这些结果确认miR-378(STAR)是一个分子开关，通过干扰整合良好的生物能量学转录途径参与乳腺癌细胞中Warburg效应的编排。
Cancer cell metabolism is often characterized by a shift from an oxidative to a glycolytic bioenergetics pathway, a phenomenon known as the Warburg effect. miR-378(star) is embedded within PPARGC1b which encodes PGC-1 beta, a transcriptional regulator of oxidative energy metabolism. Here we show that miR-378(star) expression is regulated by ERBB2 and induces a metabolic shift in breast cancer cells. miR-378(star) performs this function by inhibiting the expression of two PGC-1 beta partners, ERR gamma and GABPA, leading to a reduction in tricarboxylic acid cycle gene expression and oxygen consumption as well as an increase in lactate production and in cell proliferation. In situ hybridization experiments show that miR-378(star) expression correlates with progression of human breast cancer. These results identify miR-378(star) as a molecular switch involved in the orchestration of the Warburg effect in breast cancer cells via interference with a well-integrated bioenergetics transcriptional pathway.