Targeting BMI-1-mediated epithelial-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
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（5）
• 所属期刊栏目: Original articles
• 页码范围: 1274-1285
• 页数: 12页
• 语种: 英文

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 epithelial-mesenchymal transition(EMT),while BMI-1 overexpression in low metastatic Ls174T and DLD1 cells enhanced invasiveness and EMT.The effects of BMI-1 in CRC cells were related to upregulat-ing snail via AKT/GSK-3β pathway.Furthermore,knockdown BMI-1 in HCT116 and LOVO cells reduced CRCLM using experimental liver metastasis mice model.Meanwhile,BMI-1 overexpression in Ls174Tand DLD1 significantly increased CRCLM.Moreover,sodium butyrate,a histone deacetylase and BMI-1 inhib-itor,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.