KPNA2 promotes metabolic reprogramming in glioblastomas by regulation of c-myc.
KPNA2 promotes metabolic reprogramming in glioblastomas by regulation of c-myc.
复制标题
KPNA2 通过调节 c-myc 促进胶质母细胞瘤的代谢重编程
DOI：
10.1186/s13046-018-0861-9
复制
发表时间：
2018-08-16
期刊：
影响因子：
--
通讯作者：
Xin T
中科院分区：
文献类型：
--
作者：
Li J;Liu Q;Liu Z;Xia Q;Zhang Z;Zhang R;Gao T;Gu G;Wang Y;Wang D;Chen X;Yang Y;He D;Xin T
研究背景癌细胞主要通过糖酵解来维持能量代谢，即使在充足的氧气条件下也是如此。它使癌细胞在复杂的内部环境下更好地生长。KPNA 2是近年来备受关注的新癌基因，但其在肿瘤发生发展中的确切机制尚不清楚。方法采用免疫组织化学方法检测KPNA 2在胶质母细胞瘤和正常人脑组织中的表达。采用比色法测定了糖酵解、乳酸生成和葡萄糖摄取过程中关键酶的活性。通过流式细胞术测量GLUT-1表达。采用CCK-8检测细胞活力，建立裸鼠移植瘤模型，探讨KPNA-2在体内的作用。另外，采用Co-IP、亚细胞分级分离、Western blot、免疫荧光和荧光素酶分析等方法研究KPNA 2、c-myc和E2 F1之间的内在联系。KPNA 2水平是胶质瘤患者预后的独立预测因子。在胶质母细胞瘤细胞系U87和U251中敲低KPNA 2降低脱氧葡萄糖摄取、关键糖酵解酶的活性和乳酸产生。氧化磷酸化（OXPHOS）水平中度降低。此外，肿瘤增殖和侵袭性也同时下调。我们已经确定c-myc作为KPNA 2的潜在介导者。KPNA 2的异常表达显著改变了c-myc的亚细胞分布及其表达水平。E2 F1是KPNA 2的另一个关键货物蛋白，在KPNA 2对c-myc转录的调控中可能发挥作用。结论KPNA 2是一个潜在的肿瘤癌基因，其功能部分是通过c-myc信号轴调控细胞代谢而实现的。这为瓦尔堡效应提供了一种可能的解释，从而为KPNA 2在胶质瘤发生中的作用提供了一个新的视角。
BackgroundCancer cells maintain energy metabolism mainly by glycolysis, even under sufficient oxygen conditions. It gives cancer cells better growth advantages under complicated internal environment. KPNA2 is a novel oncogene that has received much attention in recent years, but the exact mechanisms of KPNA2 in tumorigenesis and progression are largely unknown. Especially its potential roles in the metabolic transformation of tumors still remain to be explored.MethodsThe expressions of KPNA2 in glioblastoma and normal human brain samples were analyzed by immunohistochemical analysis. The activities of key enzymes in glycolysis, the production of lactate acid and glucose uptake were investigated by colorimetry. GLUT-1 expression was measured by flow cytometry. CCK8 was used to examine the cell viability in vitro, and the xenograft models in nude mice were established to explore the roles of KPNA2 in vivo. In addition, Co-IP, subcellular fractionation, western blot, immunofluorescence and luciferase assay were used to investigate the internal connection between KPNA2, c-myc and E2F1.ResultsIn the present study, we found that KPNA2 was highly expressed in the glioma compared to the normal brain tissues. Level of KPNA2 was an independent predictor of prognosis in the glioma patients. Knockdown of KPNA2 in the glioblastoma cell lines U87 and U251 decreased deoxyglucose uptake, activities of the key glycolytic enzymes and lactate production. The level of oxidative phosphorylation (OXPHOS) was moderately decreased. Additioanlly, tumor proliferation and invasiveness were concomitantly downregulated. We have identified c-myc as a potential mediator of KPNA2. Aberrant expression of KPNA2 significantly changed the subcellular distribution of c-myc as well as its expression level. E2F1, another key cargo protein of KPNA2, was further identified to play a potential role in regulating the transcription of c-myc by KPNA2.ConclusionsOur findings suggested that KPNA2, a potential tumor oncogene, performs its function in part via regulating cellular metabolism through c-myc signaling axis. It would provide a possible explanation for Warburg effect and thus offer a new perspective to the roles of KPNA2 in gliomagenesis.
登录
查看更多内容
DOI：
10.1073/pnas.86.10.3594
发表时间：
1989-05-01
影响因子：
11.1
作者：
HIEBERT, SW;LIPP, M;NEVINS, JR
通讯作者：
NEVINS, JR
影响因子：
5.3
作者：
Dimri, GP;Itahana, K;Campisi, J
通讯作者：
Campisi, J
影响因子：
6.4
作者：
Grupp, Katharina;Boumesli, Rebecca;Quaas, Alexander
通讯作者：
Quaas, Alexander
影响因子：
3.7
作者：
Brown DV;Filiz G;Daniel PM;Hollande F;Dworkin S;Amiridis S;Kountouri N;Ng W;Morokoff AP;Mantamadiotis T
通讯作者：
Mantamadiotis T
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.