MUC1在HER2阳性乳腺癌发病中的作用及机制研究  

Mechanism of MUC1 in the pathogenesis of HER2-positive breast cancer

作　　者：王成志[1] 邓华云 庞智 黄雷[1] WANG Cheng-zhi;DENG Hua-yun;PANG Zhi;HUANG Lei(Department of Histoembryology,Genetics and Developmental Biology,Shanghai Jiao Tong University College of Basic Medical Sciences,Shanghai 200025,China)

机构地区：[1]上海交通大学基础医学院组织胚胎学与遗传发育学系,上海200025

出　　处：《上海交通大学学报（医学版）》2021年第7期839-848,共10页Journal of Shanghai Jiao tong University:Medical Science

基　　金：国家自然科学基金(82073111,81874197);上海交通大学医学院高水平地方高校创新团队(SSMU-ZLCX20180102)。

摘　　要：目的·研究黏蛋白1(mucin 1,MUC1)在人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)阳性乳腺癌发病中的作用及其调控的分子机制。方法·使用病毒感染技术构建MT2/MUC1诱导表达细胞株和MT2/Vec及MT2/CD过表达细胞株;采用蛋白质印迹法(Western blotting)检测过表达MUC1和MUC1-CD后6-磷酸葡萄糖脱氢酶(glucose-6-phosphate 1-dehydrogenase,G6PD)的蛋白质表达水平;通过细胞计数试剂盒8(cell counting kit-8,CCK-8)法、平板克隆形成实验、细胞划痕实验、Transwell迁移实验和肿瘤细胞成球实验,研究MUC1对HER2阳性乳腺癌细胞MT2增殖、克隆形成、迁移和成球的影响;使用GP6D的抑制剂6-AN抑制酶活性,CCK-8检测乳腺癌细胞增殖;采用GEPIA和Kaplan-Meier Plotter数据库分析HER2、MUC1和G6PD在乳腺癌中的表达及其对乳腺癌患者生存期的影响。结果·过表达MUC1或MUC1-CD促进HER2阳性乳腺癌细胞MT2的增殖、克隆形成、迁移和成球,并且提高G6PD的蛋白质表达水平。抑制G6PD活性显著降低MUC1和MUC1-CD诱导的细胞增殖。G6PD蛋白在乳腺癌组织中表达上调且与乳腺癌患者生存期缩短相关。结论·MUC1可能通过调控G6PD的表达促进HER2阳性乳腺癌的进程,提示抑制磷酸戊糖途径可能成为HER2阳性乳腺癌治疗的靶点。Objective·To study the role and mechanism of mucin 1(MUC1)in the pathogenesis of HER2-positive breast cancer.Methods·Virus infection technology was employed to construct MT2/MUC1 and MT2/Vec/MUC1-CD overexpression cell lines;Western blotting was used to detect the expression level of relative proteins;the ability of cell proliferation,migration and sphere formation were detected by using cell counting kit-8(CCK-8),colony formation,wound healing,transwell and sphere formation experiments respectively;inhibitor 6-AN was used to inhibit glucose-6-phosphate 1-dehydrogenase(G6PD)activity,and the proliferation of breast cancer cells was detected by CCK-8.GEPIA and Kaplan-Meier Plotter database were analyzed to figure out the relationship of HER2,MUC1 and G6PD expression with the survival of breast cancer patients.Results·Overexpression of MUC1 or MUC1-CD promoted the proliferation,clone formation,migration and sphere formation of MT2 HER2-positive breast cancer cells,as well as elevating the protein level of G6PD.Inhibition of G6PD activity significantly reduced cell proliferation induced by MUC1 and MUC1-CD.High level of G6PD protein in breast cancer tissues is associated with significantly lower survival of breast cancer patients.Conclusion·MUC1 may promote the progression of HER2-positive breast cancer by up-regulating the expression of G6PD,suggesting that inhibition of the pentose phosphate pathway may be a target for the treatment of HER2-positive breast cancer.

关 键 词：乳腺癌 黏蛋白1 磷酸戊糖途径 6-磷酸葡萄糖脱氢酶 

分 类 号：R737.9[医药卫生—肿瘤]