The PIK3CA E542K and E545K mutations promote glycolysis and proliferation via induction of the -catenin/SIRT3 signaling pathway in cervical cancer
The PIK3CA E542K and E545K mutations promote glycolysis and proliferation via induction of the -catenin/SIRT3 signaling pathway in cervical cancer
复制标题
PIK3CA E542K 和 E545K 突变通过诱导宫颈癌中的 β-catenin/SIRT3 信号通路促进糖酵解和增殖。
DOI：
10.1186/s13045-018-0674-5
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发表时间：
2018-12-14
影响因子：
28.5
通讯作者：
Yang, Huijuan
中科院分区：
文献类型：
--
作者：
Jiang, Wei;He, Tiancong;Yang, Huijuan
背景本研究旨在探讨PIK 3CA E542 K和E545 K突变对宫颈癌糖代谢和细胞增殖的影响及其机制。在体外，使用糖酵解分析、细胞外酸化速率分析和ATP产生来评估PIK 3CA E542 K和E545 K突变对葡萄糖代谢的影响。分别采用免疫印迹法和免疫组化法检测宫颈癌细胞和肿瘤组织中关键糖酵解酶的表达水平。免疫荧光法观察β-catenin的核转位。用荧光素酶报告系统分析β-连环蛋白的靶基因。结果突变型PIK 3CA（E542 K和E545 K）的宫颈癌患者的SUVmax值高于野生型PIK 3CA患者（P=0.037），这在异种移植模型中得到证实。在体外，在具有突变体PIK 3CA的SiHa和MS 751细胞中观察到增强的葡萄糖代谢和增殖。关键糖酵解酶的mRNA和蛋白质表达增加。AKT/GSK 3/β-catenin信号在具有突变PIK 3CA的SiHa和MS 751细胞中高度活化。敲低β-连环蛋白表达降低葡萄糖摄取和乳酸产生。此外，在SiHa细胞和具有突变PIK 3CA的肿瘤中发现β-连环蛋白的核积聚。此外，β-catenin下调SIRT 3的表达，通过抑制SIRT 3启动子的活性，和减少葡萄糖摄取和乳酸生产由于β-catenin的下调可以逆转SIRT 3 siRNA转染SiHa细胞与突变PIK 3CA。结论PI 3 K/E542 K和E545 K/-catenin/SIRT 3信号轴调节PIK 3CA突变的宫颈癌细胞的糖代谢和增殖，为宫颈癌的治疗提供了新的靶点。于二零一二年十二月二十四日注册（追溯注册）。
BackgroundThe study aims to present the effect of PIK3CA E542K and E545K mutations on glucose metabolism and proliferation and identify their underlying mechanisms in cervical cancer.MethodsThe maximum standard uptake value (SUVmax) of tumors was detected by(18)F-FDG PET/CT scan. In vitro, glycolysis analysis, extracellular acidification rate analysis, and ATP production were used to evaluate the impact of PIK3CA E542K and E545K mutations on glucose metabolism. The expression level of key glycolytic enzymes was evaluated by western blotting and immunohistochemical staining in cervical cancer cells and tumor tissues, respectively. Immunofluorescence analysis was used to observe the nuclear translocation of -catenin. The target gene of -catenin was analyzed by using luciferase reporter system. The glucose metabolic ability of the xenograft models was assessed by SUVmax from microPET/CT scanning.ResultsCervical cancer patients with mutant PIK3CA (E542K and E545K) exhibited a higher SUVmax value than those with wild-type PIK3CA (P=0.037), which was confirmed in xenograft models. In vitro, enhanced glucose metabolism and proliferation was observed in SiHa and MS751 cells with mutant PIK3CA. The mRNA and protein expression of key glycolytic enzymes was increased. AKT/GSK3/-catenin signaling was highly activated in SiHa and MS751 cells with mutant PIK3CA. Knocking down -catenin expression decreased glucose uptake and lactate production. In addition, the nuclear accumulation of -catenin was found in SiHa cells and tumors with mutant PIK3CA. Furthermore, -catenin downregulated the expression of SIRT3 via suppressing the activity of the SIRT3 promotor, and the reduced glucose uptake and lactate production due to the downregulation of -catenin can be reversed by the transfection of SIRT3 siRNA in SiHa cells with mutant PIK3CA. The negative correlation between -catenin and SIRT3 was further confirmed in cervical cancer tissues.ConclusionsThese findings provide evidence that the PI3K E542K and E545K/-catenin/SIRT3 signaling axis regulates glucose metabolism and proliferation in cervical cancers with PIK3CA mutations, suggesting therapeutic targets in the treatment of cervical cancers.Trial registrationFUSCC 050432-4-1212B. Registered 24 December 2012 (retrospectively registered).