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

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

doi:10.1016/j.apsb.2020.11.018

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

Acta Pharm Sin B. 2021 May;11(5):1274-1285. doi: 10.1016/j.apsb.2020.11.018. Epub 2020 Nov 28.

Authors

Zhiyao Xu^{1

2}, Zhuha Zhou³, Jing Zhang¹, Feichao Xuan⁴, Mengjing Fan^{1

2}, Difan Zhou⁴, Zhenyu Liuyang⁴, Ximei Ma⁴, Yiyang Hong¹, Yihong Wang², Sherven Sharma⁵, Qinghua Dong^{1

6}, Guanyu Wang⁴

Affiliations

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 Geffen 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.

Abstract

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 upregulating 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 Ls174T 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.

Keywords: AKT; ANOVA, One-way analysis of variance; BMI-1; CRC, colorectal cancer; CRCLM, colorectal cancer liver metastasis; Colorectal cancer; EMT, epithelial–mesenchymal transition; Epithelial–mesenchymal transition; GSK-3β; HDACi, histone deacetylase inhibitor; HE, hematoxylin and eosin; IHC, immunohistochemistry; LNM, lymph node metastasis; Liver metastasis; NaB, sodium butyrate; PBS, phosphate buffered solution; PcG, polycomb-group; Snail; Sodium butyrate; TCGA, Cancer Genome Atlas; qPCR, real time polymerase chain reaction.