MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming
MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming
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MFN1依赖性线粒体动力学改变通过葡萄糖代谢重编程驱动肝细胞癌转移
DOI：
10.1038/s41416-019-0658-4
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发表时间：
2019-12
影响因子：
8.8
通讯作者：
Qin Lun-Xiu
中科院分区：
文献类型：
--
作者：
Zhang Ze;Li Tian-En;Chen Mo;Xu Da;Zhu Ying;Hu Bei-Yuan;Lin Zhi-Fei;Pan Jun-Jie;Wang Xuan;Wu Chao;Zheng Yan;Lu Lu;Jia Hu-Liang;Gao Song;Dong Qiong-Zhu;Qin Lun-Xiu
线粒体动力学在肿瘤进展中起重要作用。然而，这些动力学在肝细胞癌（HCC）转移过程中如何整合肿瘤代谢尚不清楚。方法检测肝癌组织中线粒体融合蛋白mitofusin-1 （MFN1）的表达及其预后价值。在体外和体内分析了MFN1对HCC转移和代谢重编程的影响及其潜在机制。结果发现以持续的裂变和融合为代表的线粒体动力学与HCC转移有关。高转移性HCC表现为线粒体分裂过多。在参与线粒体动力学的基因中，mfn1被认为是一个主要的下调候选基因，与HCC转移和不良预后密切相关。在促进线粒体融合的同时，MFN1在体外和体内均抑制细胞增殖、侵袭和迁移能力。从机制上讲，MFN1耗竭对线粒体动力学的破坏触发了HCC的上皮-间质转化（EMT）。此外，MFN1通过从有氧糖酵解到氧化磷酸化的代谢转变来调节HCC转移。糖酵解抑制剂2-脱氧-d-葡萄糖（2-DG）可显著抑制MFN1耗竭引起的效应。结论线粒体动力学通过调节葡萄糖代谢重编程参与HCC转移。MFN1可能成为HCC新的潜在治疗靶点。
BackgroundMitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear.MethodsThe mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo.ResultsMitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics,MFN1is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1.ConclusionsOur results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC.
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DOI：
10.1016/j.tem.2017.06.004
发表时间：
2017-10
期刊：
Trends in endocrinology and metabolism: TEM
影响因子：
--
作者：
Valcarcel-Jimenez L;Gaude E;Torrano V;Frezza C;Carracedo A
通讯作者：
Carracedo A
影响因子：
11.4
作者：
Salimi A;Roudkenar MH;Sadeghi L;Mohseni A;Seydi E;Pirahmadi N;Pourahmad J
通讯作者：
Pourahmad J
DOI：
10.1083/jcb.201210045
发表时间：
2013-06-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Strack S;Wilson TJ;Cribbs JT
通讯作者：
Cribbs JT
影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
GOLM1 调节 EGFR/RTK 细胞表面回收以驱动肝细胞癌转移。
影响因子：
50.3
作者：
Ye QH;Zhu WW;Zhang JB;Qin Y;Lu M;Lin GL;Guo L;Zhang B;Lin ZH;Roessler S;Forgues M;Jia HL;Lu L;Zhang XF;Lian BF;Xie L;Dong QZ;Tang ZY;Wang XW;Qin LX
通讯作者：
Qin LX