Mineralocorticoid receptor suppresses cancer progression and the Warburg effect by modulating the miR-338-3p-PKLR axis in hepatocellular carcinoma.
Mineralocorticoid receptor suppresses cancer progression and the Warburg effect by modulating the miR-338-3p-PKLR axis in hepatocellular carcinoma.
复制标题
盐皮质激素受体通过调节肝细胞癌中的 miR-338-3p-PKLR 轴抑制癌症进展和 Warburg 效应
DOI：
10.1002/hep.27940
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Zhang ZG
中科院分区：
文献类型：
--
作者：
Nie H;Li J;Yang XM;Cao QZ;Feng MX;Xue F;Wei L;Qin W;Gu J;Xia Q;Zhang ZG
在正常的生理和病理条件下，激素及其相应的受体在控制新陈代谢方面是至关重要的，但对它们在癌症新陈代谢中的作用知之甚少。使用一种小干扰RNA筛选方法，我们研究了沉默20种众所周知的激素受体对Warburg效应的影响，特别是通过测量四个已建立的肝细胞癌(HCC)细胞系中乳酸的产生。我们发现，沉默多种激素受体对这种代谢物的产生有影响。出人意料的是，盐皮质激素受体(MR)的沉默显著增加了所有这些肝癌细胞系的乳酸产量。随后的体外和体内研究表明，MR功能的获得和丧失显著影响肝癌细胞的增殖、细胞周期分布和细胞凋亡。此外，机制研究表明，MR作为一种转录因子直接调节miR-338-3p的表达，通过靶向糖酵解的关键酶：丙酮酸激酶、肝脏和红细胞来抑制肝癌细胞的Warburg效应。此外，81%的肝癌患者组织中MR表达显著下调，这是由于染色体缺失和组蛋白去乙酰化所致。MR在肿瘤组织中的低表达与患者预后不良有关。研究发现，miR-338-3p在肝细胞癌组织中的表达水平与MR的表达呈正相关，与丙酮酸激酶、肝脏和红细胞的表达呈负相关。结论：MR通过调节miR-338-3p/丙酮酸激酶、肝脏和红细胞轴，抑制Warburg效应，从而影响肝癌的发生发展。(《肝病》2015；62：1145-1159)
Hormones and their corresponding receptors are vital in controlling metabolism under normal physiologic and pathologic conditions, but less is known about their roles in the metabolism of cancer. Using a small interfering RNA screening approach, we examined the effects of silencing 20 well‐known hormone receptors on the Warburg effect, specifically by measuring the production of lactate in four established hepatocellular carcinoma (HCC) cell lines. We found that silencing a variety of hormone receptors had effects on the production of this metabolite. Unexpectedly silencing of mineralocorticoid receptor (MR) significantly increased lactate production in all these HCC cell lines. Subsequent in vitro and in vivo studies showed that gain‐ and loss‐of‐function of MR significantly influenced HCC cellular proliferation, cell cycle distribution, and apoptosis. Furthermore, mechanistic studies revealed that MR as a transcriptional factor directly regulated the expression of miR‐338‐3p, suppressing the Warburg effects of HCC cells by targeting a key enzyme of glycolysis: pyruvate kinase, liver and red blood cells. Moreover, MR expression was significantly down‐regulated in 81% of HCC patient tissues, caused by both chromosome deletion and histone deacetylation. Low expression of MR in tumor tissues was associated with poor patient prognosis. The expression level of miR‐338‐3p was found to positively correlate with the expression of MR in HCC tissues and to inversely correlate with expression of the enzyme pyruvate kinase, liver and red blood cells. Conclusion: MR affects HCC development by modulating the miR‐338‐3p/pyruvate kinase, liver and red blood cells axis with an ability to suppress the Warburg effect. (Hepatology 2015;62:1145‐1159)