低氧诱导因子1α、溴结构域蛋白4对乳腺癌低氧微环境自噬水平的影响  

Effect of HIF-1α and BRD4 on autophagy level of breast cancer cell in hypoxic microenvironment

作　　者：连渊娥[1] 吴丹 黄建平[1] 郑巧灵[1] 白燕南[2] 冯昌银[1] 杨映红[1] Lian Yuane;Wu Dan;Huang Jianping;Zheng Qiaoling;Bai Yannan;Feng Changyin;Yang Yinghong(Department of Pathology,the Union Hospital of Fujian Medical University,Fuzhou 350001,China;Department of Hepatobiliopancreatic Surgery,Fujian Provincial Hospital,Fuzhou 350001,China)

机构地区：[1]福建医科大学附属协和医院病理科,福州350001 [2]福建省立医院肝胆外科,福州350001

出　　处：《中华病理学杂志》2020年第12期1294-1299,共6页Chinese Journal of Pathology

基　　金：福建省自然科学基金(2017J01817,2017J01177);福建省卫生计生青年科研课题(2014-1-47);福建医科大学启航基金项目(2016QH026)。

摘　　要：目的探讨低氧诱导因子1α(HIF-1α)、溴结构域蛋白4(BRD4)及自噬相关蛋白Beclin1、LC3B、p62在乳腺癌组织的表达及其临床病理意义,并研究低氧调控下乳腺癌细胞HIF-1α、BRD4及自噬水平的表达变化。方法采用免疫组织化学EnVision法检测125例乳腺癌组织和50例癌旁正常乳腺组织HIF-1α、BRD4、Beclin1、LC3B、p62蛋白的表达,分析其与乳腺癌临床病理特征的关系,并分析蛋白表达水平的相关性。低氧(1%O2)刺激MCF-10A、MCF-7及MDA-MB-231细胞,24 h后检测低氧对细胞HIF-1α、BRD4、Beclin1、LC3B、p62蛋白表达的影响。结果HIF-1α、BRD4、Beclin1、LC3B蛋白在乳腺癌组织中的阳性率及高表达比率显著高于癌旁正常乳腺组织,而p62蛋白的高表达比率(42.4%,53/125)低于癌旁正常乳腺组织(70.0%,35/50),差异均具有统计学意义(P<0.05)。乳腺癌组织中组织学分级越高,HIF-1α、BRD4、Beclin1、LC3B高表达率越高(P<0.05)。淋巴结转移、存在脉管瘤栓者常伴有HIF-1α、Beclin1高表达(P<0.05)。雌激素受体(ER)/孕激素受体(PR)阴性组的HIF-1α、BRD4、Beclin1、LC3B高表达比率较ER/PR阳性组增高(P<0.05)。HIF-1α高表达与HER2阳性有关(P<0.05)。HIF-1α、BRD4、Beclin1、LC3B两两之间在乳腺癌组织中的表达均存在正相关关系,差异具有统计学意义(P<0.01)。低氧刺激24 h后乳腺癌细胞的HIF-1α、BRD4、Beclin1、LC3B蛋白表达上调,p62表达下调。结论乳腺癌组织中存在低氧现象并诱导自噬。HIF-1α与BRD4表达存在正相关,提示BRD4参与了乳腺癌低氧微环境对自噬的调控。乳腺癌HIF-1α、BRD4及自噬的高表达可能在乳腺癌的发生发展过程中发挥重要作用。Objective To investigate the expressions of HIF-1α,BRD4,Beclin1,LC3B and p62 in breast cancer tissues and their clinicopathological significance,and to study alterations of their expression in breast cancer cells under hypoxic microenvironment.Methods Immunohistochemistry was used to detect HIF-1α,BRD4,Beclin1,LC3B and p62 protein expressions in 125 breast cancer tissues and 50 para-cancer normal breast tissues,and their correlation with clinicopathologic characteristics were analyzed.The expression of these proteins were also measured after 24 hours of hypoxia stimulation was detected in different breast cancer cell lines and normal breast epithelial cells.Results The expression of HIF-1α,BRD4,Beclin1 and LC3B proteins in breast cancer tissues were significantly higher than in para-cancer normal breast tissues(P<0.05).There was a positive association between histologic grade,the expression of HIF-1α,BRD4,Beclin1 and LC3B(P<0.05).High expressions of HIF-1a and Beclin1 were often correlated with lymph node metastasis and lymphatic invasion(P<0.05).Increased HIF-1α,BRD4,Beclin1 and LC3B expression was associated with ER or PR negativity,but only HIF-1αwas associated with HER2 positivity(P<0.05).HIF-1α,BRD4,Beclin1,and LC3B were positively correlated with each other in breast cancer tissues(P<0.01).After 24 hours of hypoxic stimulation,the expression of HIF-1α,BRD4,Beclin1 and LC3B was up-regulated in breast cancer cells.Conclusions Hypoxia induces autophagy in breast cancer tissues.HIF-1αis positively correlated with BRD4,suggesting that BRD4 is involved in the regulation of autophagy by hypoxic microenvironment in breast cancer.High expression of HIF-1α,BRD4 and autophagy may play an important role in the development of breast cancer.

关 键 词：乳腺肿瘤 肿瘤微环境 自噬 

分 类 号：R737.9[医药卫生—肿瘤]