Mineralocorticoid receptor modulates miR-338-3p-PKLR axis.

source:Chinese Society of Matrix Biology    add time:2016-01-15 11:27:25

Mineralocorticoid receptor suppresses cancer progression and Warburg effect by modulating miR-338-3p-PKLR axis in hepatocellular carcinoma

Nie H, Li J, Yang XM, Cao QZ, Feng MX, Xue F, Wei L, Qin W, Gu J, Xia Q, Zhang ZG*.  2015;62(4):1145-59. (*Corresponding author)
the State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China


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.


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