miR-139-5p inhibits aerobic glycolysis, cell proliferation, migration, and invasion in hepatocellular carcinoma via a reciprocal regulatory interaction with ETS1
miR-139-5p inhibits aerobic glycolysis, cell proliferation, migration, and invasion in hepatocellular carcinoma via a reciprocal regulatory interaction with ETS1
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miR-139-5p 通过与 ETS1 的相互调节相互作用抑制肝细胞癌的有氧糖酵解、细胞增殖、迁移和侵袭
DOI：
10.1038/s41388-017-0057-3
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发表时间：
2018-03-01
期刊：
影响因子：
8
通讯作者：
Wu, Dehua
中科院分区：
文献类型：
--
作者：
Hua, Shengni;Lei, Ling;Wu, Dehua
癌细胞具有代谢特征，允许它们优先通过有氧糖酵解代谢葡萄糖，为它们提供进展优势。然而，microRNA（miRNA）调节癌细胞中的有氧糖酵解尚未得到广泛研究。我们在本研究中通过使用临床标本、HCC细胞和小鼠异种移植模型来检查miR-139- 5 p对肝细胞癌（HCC）有氧糖酵解的调节来解决这一问题。我们发现，过表达miR-139- 5 p抑制有氧糖酵解，抑制肝癌细胞的增殖，迁移和侵袭。miR-139- 5 p通过直接靶向转录因子ETS 1调节己糖激酶1（HK 1）和6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3（PFKFB 3）的表达，ETS 1与HK 1和PFKFB 3基因的启动子结合。miR-139- 5 p诱导的有氧糖酵解、增殖、迁移和侵袭被ETS 1过表达逆转，而ETS 1沉默通过涉及Drosha的转录后调控模式诱导miR-139- 5 p的表达。与癌旁组织相比，HCC中miR-139- 5 p表达降低，这在癌症基因组图谱和GSE 54751 HCC队列中得到证实。值得注意的是，mir-139的低表达与较差的预后相关。这些结果表明，miR-139- 5 p和ETS 1之间的相互调节相互作用调节HCC细胞的有氧糖酵解，增殖和转移，提示HCC治疗的新靶点。
Cancer cells have metabolic features that allow them to preferentially metabolize glucose through aerobic glycolysis, providing them with a progression advantage. However, microRNA (miRNA) regulation of aerobic glycolysis in cancer cells has not been extensively investigated. We addressed this in the present study by examining the regulation of miR-139-5p on aerobic glycolysis of hepatocellular carcinoma (HCC) using clinical specimens, HCC cells, and a mouse xenograft model. We found that overexpressing miR-139-5p restrained aerobic glycolysis, suppressing proliferation, migration, and invasion in HCC cells. miR-139-5p regulated hexokinase 1 (HK1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression by directly targeting the transcription factor ETS1, which bound to the promoters of theHK1andPFKFB3genes. miR-139-5p-induced aerobic glycolysis, proliferation, migration, and invasion were reversed by ETS1 overexpression, while ETS1 silencing induced the expression of miR-139-5p via a post-transcriptional regulation mode involving Drosha. miR-139-5p expression was reduced in HCC compared to para-carcinoma tissue, which was confirmed in The Cancer Genome Atlas and GSE54751 HCC cohorts. Notably, the lower expression of mir-139 was correlated with worse prognosis. These outcomes indicate that reciprocal regulatory interactions between miR-139-5p and ETS1 modulate aerobic glycolysis, proliferation, and metastasis in HCC cells, suggesting new targets for HCC treatment.