葡萄糖6-磷酸脱氢酶调控细胞周期蛋白E1和细胞周期蛋白依赖性激酶2促进细胞增殖及其在肾透明细胞癌中的预后价值  

G6PD Regulates Cyclin E1 and CDK2 to Promote Cell Proliferation and Its Prognostic Value in Clear Cell Renal Cell Carcinoma

作　　者：杨哲 倪月莉[1] 王舒婕 刘文静 朱玉芝 车蓉 段友斌 况应敏 朱月春[1] 张巧 YANG Zhe;NI Yue-Li;WANG Shu-Jie;LIU Wen-Jing;ZHU Yu-Zhi;CHE Rong;DUAN You-Bin;KUANG Ying-Min;ZHU Yue-Chun;ZHANG Qiao(Department of Biochemistry and Molecular Biology,School of Basic Medicine,Kunming Medical University,Kunming 650500,China;Department of Pathology,First Affiliated Hospital of Kunming Medical University,Kunming 650032,China;Department of Biochemistry and Molecular Biology,School of Basic Medicine,Peking University,Beijing 100191,China;Department of Pediatrics,School of Clinic,Qujing Medical College,Qujing 655000,Yunnan,China;Kunming Blood Center,Kunming 650106,China;Department of Organ Transplant,First Affiliated Hospital of Kunming Medical University,Kunming 650032,China)

机构地区：[1]昆明医科大学基础医学院生物化学与分子生物系,昆明650500 [2]昆明医科大学第一附属医院病理科,昆明650032 [3]北京大学基础医学院生物化学与分子生物学系,北京100191 [4]曲靖医学高等专科学校临床学院儿科,云南曲靖655000 [5]昆明市血液中心,昆明650106 [6]昆明医科大学第一附属医院器官移植科,昆明650032

出　　处：《中国生物化学与分子生物学报》2022年第5期658-670,共13页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金(No.31960145,81560037,82103388,81660135)资助。

摘　　要：肾透明细胞癌(clear cell renal cell carcinoma,ccRCC)是一种转移率高、预后差的细胞代谢性疾病,对其有效诊疗及预后分子标志物的研究十分重要。葡萄糖6-磷酸脱氢酶(glucose 6-phosphatedehydrogenase,G6PD)在ccRCC中高表达,并提示患者不良预后,其促进ccRCC细胞增殖的分子机制有待进一步揭示。本研究发现,降低G6PD可抑制细胞周期G_(1)/S期转化并显著抑制ccRCC细胞增殖。G6PD可在细胞水平调控G_(1)/S期转化及增殖相关因子Cyclin D1,CDK4,CDK6,Cyclin E1和CDK2基因表达。TCGA数据库分析结果表明,ccRCC中Cyclin D1,Cyclin E1和CDK2的mRNA水平显著升高,而CDK4表达无明显差异,CDK6表达却显著降低。相关性分析结果显示,G6PD与Cyclin D1呈显著负相关(P<0.0001),G6PD与CDK4,CDK6之间无显著相关性(P>0.05),G6PD与Cyclin E1(P<0.0001)以及CDK2(P<0.05)显著正相关。进一步免疫组化检测结果表明,Cyclin E1和CDK2在ccRCC肿瘤组织中表达显著升高。生存预后分析结果显示,Cyclin D1高表达提示ccRCC患者整体预后更为良好,CDK4和CDK6表达水平在ccRCC患者总生存率预测中无意义;而Cyclin E1和CDK2高表达均可提示ccRCC患者预后不良。进一步细胞水平检测发现,Cyclin E1、CDK2表达降低可显著逆转G6PD促进ccRCC细胞增殖的能力。综上,与增殖相关因子Cyclin D1,CDK4和CDK6相比,G6PD有可能通过促进Cyclin E1和CDK2表达升高而发挥促进ccRCC肿瘤细胞增殖的作用,并且这3者的异常高表达有望成为ccRCC患者不良预后的独立生存预测因素。Clear cell renal cell carcinoma(ccRCC)has been proved to be a metabolic disease with high metastasis rate and poor prognosis.Effective molecular markers for diagnosis,treatment and prognosis are very important for this disease.Glucose 6-phosphatedehydrogenase(G6PD)was highly expressed in ccRCC and suggested a poor prognosis.The molecular mechanism of its promotion of ccRCC cell proliferation needs to be unraveled.The purpose of this study was to investigate the regulatory effect of G6PD on the expression of Cyclin E1 and CDK2,and to reveal the prognostic value of G6PD,Cyclin E1 and CDK2 in ccRCC patients.Our results demonstrated that decreasing G6PD could inhibit G_(1)/S phase transformation and ccRCC cell proliferation.G6PD regulated the expression of G_(1)/S phase transformation and proliferation related genes,including Cyclin D1,CDK4,CDK6,Cyclin E1 and CDK2.Through TCGA dataset mining,the results showed that compared with the normal control group,the mRNA levels of Cyclin D1,Cyclin E1 and CDK2 were significantly increased in ccRCC,but the expression of CDK6 was significantly decreased and no change of the expression of CDK4.G6PD was negatively correlated with Cyclin D1(P<0.0001).There was no significant correlation between G6PD and CDK4 or CDK6(P>0.05).G6PD and Cyclin E1(P<0.0001),G6PD and CDK2(P<0.05)were positively correlated.The results of immunohistochemical analysis demonstrated that Cyclin E1 and CDK2 protein expression levels were significantly increased in ccRCC tumor tissues compared with adjacent normal tissues.Kaplan-Meier and Cox regression analysis showed that high expression of Cyclin D1 rather suggested a better overall prognosis in ccRCC patients,and the expression levels of CDK4 and CDK6 were not significant in predicting the overall survival rate of ccRCC patients.However,high expression of Cyclin E1 and CDK2 indicated poor prognosis in ccRCC patients.Further cell model analyses indicated that decreased expression of Cyclin E1 and CDK2 could significantly reverse the ability of G6PD in promot

关 键 词：肾透明细胞癌 葡萄糖-6-磷酸脱氢酶 细胞周期蛋白 E1 细胞周期蛋白依赖性激酶2 增殖 

分 类 号：R737.11[医药卫生—肿瘤]