Targeting BMI-1-mediated epitheliale-mesenchymal transition to inhibit colorectal cancer liver metastasis  

作　　者：Zhiyao Xu Zhuha Zhou Jing Zhang Feichao Xuan Mengjing Fan Difan Zhou Zhenyu Liuyang Ximei Ma Yiyang Hong Yihong Wang Sherven Sharma Qinghua Dong Guanyu Wang 

机构地区：[1]Biomedical Research Center,Sir Run Run Shaw Hospital,School of Medicine,Zhejiang University,Hangzhou 310016,China [2]Department of Pathology,Sir Run Run Shaw Hospital,School of Medicine,Zhejiang University,Hangzhou 310016,China [3]Department of Gastrointestinal Surgery,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325000,China [4]Department of General Surgery,Sir Run Run Shaw Hospital,School of Medicine,Zhejiang University,Hangzhou 310016,China [5]David Gejfen School of Medicine at UCLA,and the Veterans Affairs,Los Angeles,CA 90095,USA [6]Key Laboratory of Cancer Prevention and Intervention,China National Ministry of Education,Hangzhou 310009,China

出　　处：《Acta Pharmaceutica Sinica B》2021年第5期1274-1285,共12页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.81272493 and 81472213);the Health Commission of Zhejiang Province(Nos.2019331258 and 2019335600,China);Natural Sciences Foundation of Zhejiang Province(No.LY17H220001,China);the Science Technology Department of Zhejiang Province(Nos.LGF20H220001 and 2015C37112,China)。

摘　　要：Liver is the most common metastatic site for colorectal cancer(CRC),there is no satisfied approach to treat CRC liver metastasis(CRCLM).Here,we investigated the role of a polycomb protein BMI-1 in CRCLM.Immunohistochemical analysis showed that BMI-1 expression in liver metastases was upregulated and associated with T4 stage,invasion depth and right-sided primary tumor.Knockdown BMI-1 in high metastatic HCT116 and LOVO cells repressed the migratory/invasive phenotype and reversed epithelialemesenchymal transition(EMT),while BMI-1 overexpression in low metastatic Ls174 T and DLD1 cells enhanced invasiveness and EMT.The effects of BMI-1 in CRC cells were related to upregulating snail via AKT/GSK-3βpathway.Furthermore,knockdown BMI-1 in HCT116 and LOVO cells reduced CRCLM using experimental liver metastasis mice model.Meanwhile,BMI-1 overexpression in Ls174 T and DLD1 significantly increased CRCLM.Moreover,sodium butyrate,a histone deacetylase and BMI-1 inhibitor,reduced HCT116 and LOVO liver metastasis in immunodeficient mice.Our results suggest that BMI-1 is a major regulator of CRCLM and provide a potent molecular target for CRCLM treatment.

关 键 词：BMI-1 Colorectal cancer Liver metastasis Epitheliale-mesenchymal transition SNAIL AKT GSK-3b Sodium butyrate 

分 类 号：R735.34[医药卫生—肿瘤]