目的 分析ATP5A1在胃癌中的表达及对患者预后的影响,并探讨其调控肿瘤细胞糖代谢的作用机制.方法 回顾性分析2013年2月～2016年11月在我院行胃癌根治术的115例患者,检测ATP5A1在胃癌组织中的表达情况并以IOD值中位数为界,将样本分为ATP5A1高表达组(n=58)和ATP5A1低表达组(n=57),分析其对患者术后远期预后的影响;慢病毒转染技术调控胃癌细胞系(MGC803)中ATP5A1基因的表达,并探究其对胃癌细胞糖代谢的影响及可能的分子机制;将裸鼠随机分成对照组、ATP5A1过表达组和低表达组(3只/组).收集对照组、敲低和过表达ATP5A1基因的胃癌细胞悬液,分别接种到对应组裸鼠背部皮下,构建裸鼠移植瘤模型分析ATP5A1对肿瘤生长和糖代谢的影响.结果 ATP5A1在胃癌组织中高表达(P<0.05),并与外周血CEA、CA19-9,病理分级、T分期及N分期密切相关(P<0.05);而高表达组患者术后5年生存率低(P<0.001),且ATP5A1高表达是影响胃癌患者术后生存期的独立危险因素(P<0.05);ROC曲线表明,ATP5A1高表达对患者预后具有预判价值(P<0.001).过表达ATP5A1上调胃癌细胞对葡萄糖摄取和乳酸生成量以及糖代谢关键酶HK2、PFK1、LDHA的蛋白水平(P<0.05),而干扰ATP5A1则结果相反(P<0.05);在体实验表明,ATP5A1过表达增加胃癌细胞糖代谢(P<0.05),且促进肿瘤的生长(P<0.05).高表达ATP5A1促进胃癌细胞中p-JNK和p-JUN的表达(P<0.05),且JNK抑制剂SP600125阻遏了过表达ATP5A1胃癌细胞糖代谢的促进作用(P<0.05).结论 胃癌组织中ATP5A1高表达并影响患者远期预后不良,且至少部分是通过JNK/JUN通路促进胃癌细胞的糖代谢.
Objective To analyze the expression level of ATP5A1 in gastric carcinoma and its influence on the prognosis of the patients and glucose metabolism in the tumor cells.Methods We retrospectively analyzed the data of 115 patients undergoing radical resection of gastric carcinoma in our hospital from February,2013 to November,2016.ATP5A1 expression in the surgical specimens were detected using immunohistochemistry,and the long-term prognosis of the patients with high(n=58)and low ATP5A1 expression(n=57)were analyzed.In gastric carcinoma MGC803 cells,the effects of lentivirus-mediated ATP5A1 knockdown or overexpression on glucose metabolism were investigated.We also observed the growth and glucose metabolism of xenografts derived from MGC803 cells with ATP5A1 knockdown or overexpression in nude mice.Results ATP5A1 was significantly overexpressed in gastric carcinoma tissues in close correlation with blood CEA and CA19-9 levels,pathological grade,T stage and N stage(P<0.05).ATP5A1 overexpression was an independent risk factor for a significantly lowered 5-year survival rate of patients with gastric carcinoma(P<0.05).ROC curve analysis demonstrated the predictive value of high ATP5A1 expression for the patients'prognosis(P<0.001).In MGC803 cells,ATP5A1 overexpression significantly up-regulated cellular glucose uptake and lactate production and increased the protein levels of HK2,PFK1,and LDHA(P<0.05),while ATP5A1 knockdown produced the opposite changes(P<0.05).In the tumor-bearing mice,overexpression of ATP5A1 increased glucose metabolism of the tumor cells and promoted tumor growth(P<0.05).Overexpression of ATP5A1 promoted the expressions of p-JNK and p-JUN in MGC803 cells(P<0.05),and the JNK inhibitor SP600125 significantly inhibited the enhancement of cellular glucose metabolism induced by ATP5A1 overexpression(P<0.05).Conclusion High ATP5A1 expression in gastric cancer is associated a poor long-term prognosis of the patients,and its effect is mediated at least partly by promoting glucose metabolism of the cells through the JNK/JUN pathway.
杨晶晶;左芦根;殷丽霞;段婷;牛民主;何震东;陈心蕊;张小凤;李静;耿志军
蚌埠医科大学第一附属医院 胃肠外科,安徽 蚌埠 233004||蚌埠医科大学临床医学院,安徽 蚌埠 233030蚌埠医科大学第一附属医院 胃肠外科,安徽 蚌埠 233004||炎症相关性疾病基础与转化研究安徽省重点实验室,安徽 蚌埠 233004蚌埠医科大学检验医学院,安徽 蚌埠 233030||蚌埠医科大学第一附属医院检验科,安徽 蚌埠 233004蚌埠医科大学临床医学院,安徽 蚌埠 233030||蚌埠医科大学第一附属医院急诊内科,安徽 蚌埠 233004蚌埠医科大学检验医学院,安徽 蚌埠 233030蚌埠医科大学临床医学院,安徽 蚌埠 233030蚌埠医科大学第一附属医院中心实验室,安徽 蚌埠 233004||炎症相关性疾病基础与转化研究安徽省重点实验室,安徽 蚌埠 233004蚌埠医科大学第一附属医院检验科,安徽 蚌埠 233004||炎症相关性疾病基础与转化研究安徽省重点实验室,安徽 蚌埠 233004
ATP5A1;胃癌;糖代谢;预后;JNK/JUN通路
ATP5A1;gastric carcinoma;glucose metabolism;prognosis;JNK/JUN pathway
《南方医科大学学报》 2024 (005)
974-980 / 7
安徽省卫生健康科研项目(AHWJ2022a019);蚌埠医学院第一附属医院杰出青年基金(2019byyfyjq01);安徽省高校优秀青年人才支持计划重点项目(gxyqZD2022066)
10.12122/j.issn.1673-4254.2024.05.20
评论