Long-term exposure to genistein inhibits the proliferation of gallbladder cancer by downregulating the MCM complex  

大豆异黄酮genistein的长期暴露通过下调MCM复合物抑制胆囊癌增殖的研究

作　　者：Yajun Geng Shili Chen Yang Yang Huijie Miao Xuechuan Li Guoqiang Li Jian Ma TongZhang Tai Ren Yongsheng Li Lin Li Liguo Liu Jiahua Yang Ziyi Wang Lu Zou Ke Liu Yang Li Siyuan Yan Xuya Cui Xuheng Sun Bo Yang Lingxiao Zhang Xusheng Han Chuanlei Wang BoChen Xueliang Yue Wei Liang Jianjun Ren Jianguang Jia Jianfeng Gu Zhizhen Li Tiansuo Zhao Peng Wang Dong Wei Shimei Qiu Dongxi Xiang Xinsen Xu Wei Chen Min He Linhua Yang Hui Wang Tao Chen Rong Hua Xu’an Wang Xiangsong Wu Wei Gong Guangyi Wang Maolan Li Wei Zhang Rong Shao Wenguang Wu Yingbin Liu 耿亚军;陈世礼;杨洋;苗慧洁;李雪川;李国强;马建;张彤;任泰;李永盛;李霖;刘立果;杨佳华;王子逸;邹路;刘珂;李洋;严思远;崔旭雅;孙旭恒;杨波;张凌宵;韩旭晟;王传磊;陈勃;岳学良;梁威;任建军;贾建光;顾剑峰;李志臻;赵天锁;王鹏;魏东;邱世梅;向冬喜;许鑫森;陈炜;何敏;杨林华;王辉;陈涛;花荣;王许安;吴向嵩;龚伟;王广义;李茂岚;张薇;邵荣;吴文广;刘颖斌(Department of Biliary-Pancreatic Surgery,Ren Ji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China;Department of General Surgery,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China;Shanghai Key Laboratory of Biliary Tract Disease Research,Shanghai 200127,China;Department of Hepatobiliary Surgery,Affiliated Hospital of Jining Medical University,Jining 272129,China;Department of General Surgery,The Affiliated Hospital of Inner Mongolia Medical University,Hohhot 010050,China;Department of Hepatobiliary and Pancreatic Surgery,The First Hospital of Jilin University,Changchun 130021,China;Department of Hepatobiliary and Pancreatic Surgery,Henan Provincial People’s Hospital,Zhengzhou 450003,China;Department of Surgical Oncology,First Affiliated Hospital of Bengbu Medical College,Bengbu 233099,China;Department of General Surgery,Changshu No.1 People’s Hospital Affiliated to Soochow University,Changshu 215500,China;Department of Biliary Surgery,Eastern Hepatobiliary Surgery Hospital,Shanghai 200433,China;Department of Pancreatic Cancer,Tianjin Medical University Cancer Institute and Hospital,Tianjin 300060,China;Department of Hepatobiliary Surgery,Affiliated Hospital of Nantong University,Nantong 226001,China;State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology,Shanghai Cancer Institute,Shanghai 200127,China;Department of Pharmacology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;State Key Laboratory of Oncogenes and Related Genes,Shanghai

机构地区：[1]Department of Biliary-Pancreatic Surgery,Ren Ji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China [2]Department of General Surgery,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China [3]Shanghai Key Laboratory of Biliary Tract Disease Research,Shanghai 200127,China [4]Department of Hepatobiliary Surgery,Affiliated Hospital of Jining Medical University,Jining 272129,China [5]Department of General Surgery,The Affiliated Hospital of Inner Mongolia Medical University,Hohhot 010050,China [6]Department of Hepatobiliary and Pancreatic Surgery,The First Hospital of Jilin University,Changchun 130021,China [7]Department of Hepatobiliary and Pancreatic Surgery,Henan Provincial People’s Hospital,Zhengzhou 450003,China [8]Department of Surgical Oncology,First Affiliated Hospital of Bengbu Medical College,Bengbu 233099,China [9]Department of General Surgery,Changshu No.1 People’s Hospital Affiliated to Soochow University,Changshu 215500,China [10]Department of Biliary Surgery,Eastern Hepatobiliary Surgery Hospital,Shanghai 200433,China [11]Department of Pancreatic Cancer,Tianjin Medical University Cancer Institute and Hospital,Tianjin 300060,China [12]Department of Hepatobiliary Surgery,Affiliated Hospital of Nantong University,Nantong 226001,China [13]State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology,Shanghai Cancer Institute,Shanghai 200127,China [14]Department of Pharmacology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [15]State Key Laboratory of Oncogenes and Related Genes,Shanghai Cancer Institute,Shanghai 200127,China

出　　处：《Science Bulletin》2022年第8期813-824,M0003,共13页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(2019XH004,81874181,82073206,21705108,and 81773043);the Emerging Frontier Program of Hospital Development Centre(SHDC12018107);the Key Program of Shanghai Science and Technology Commission(YDZX20193100004049);the State Key Laboratory of Oncogenes and Related Genes(KF2120);the National Key Research and Development Program of China(2021YFE0203300);the Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission(20SG14);he Program of Shanghai Academic Research Leader(19XD1422700)。

摘　　要：Soy isoflavones are natural tyrosine kinase inhibitors closely associated with decreased morbidity and mortality of various tumors.The activation of tyrosine kinases such as ERBB2 is the mechanism by which cholecystitis transforms into gallbladder cancer(GBC),therefore,it is important to investigate the relationship between long-term exposure to soy isoflavones and the occurrence and progression of GBC.This case-control study(n=85 pairs)found that the high level of plasma soy isoflavoneDgenistein(GEN)was associated with a lower risk of gallbladder cancer(≥326.00 ng/m L compared to≤19.30ng/m L,crude odds ratio 0.15,95%CI 0.04–0.59;P for trend=0.016),and that the level of GEN exposure negatively correlated with Ki67 expression in GBC tissue(n=85).Consistent with these results,the proliferation of GBC cells was inhibited in the long-term exposure models of GEN in vitro and in vivo.The long-term exposure to GEN reduced the tyrosine kinase activity of ERBB2 and impaired the function of the PTK6-AKT-GSK3βaxis,leading to downregulation of the MCM complex in GBC cells.In summary,long-term exposure to GEN associated with soy products intake might play a certain role in preventing GBC and even inhibiting the proliferation of GBC cells.大豆异黄酮是天然的酪氨酸激酶抑制剂,与多种肿瘤发病率和死亡率的降低密切相关.同时,酪氨酸激酶如ERBB2的激活是胆囊炎转化为胆囊癌的重要机制,因此,研究长期接触大豆异黄酮与胆囊癌的发生和发展之间的关系十分重要.这项85对的病例对照研究发现,高血浆大豆异黄酮genistein水平与较低的胆囊癌风险相关(≥326.0与≤19.3 ng/mL对比,OR=0.15,95%可信区间0.04~0.59;趋势检验P=0.016),并且genistein暴露水平与胆囊癌组织中Ki67表达负相关(85例).与这些结果一致,体外和体内的长期genistein暴露模型中,胆囊癌细胞的增殖受到抑制.长期暴露于genistein降低了ERBB2的酪氨酸激酶活性,并影响了PTK6-AKT-GSK3β轴的功能,导致胆囊癌细胞中MCM复合物的表达下调.总之,长期接触与大豆制品摄入相关的genistein可能在预防甚至抑制胆囊癌的增殖方面起到一定的作用.

关 键 词：Gallbladder cancer Dietary exposure GENISTEIN ERBB2 pathway activation MCM protein complex 

分 类 号：TS201.4[轻工技术与工程—食品科学] R735.8[轻工技术与工程—食品科学与工程]