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

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-3 β 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.

Roles of BMI1 in the Initiation, Progression, and Treatment of Hepatocellular Carcinoma

“… 86 Interestingly, the short-chain fatty acid sodium butyrate (NaB) produced by bacterial fermentation of dietary fiber in the colon limits colorectal cancer liver metastasis by downregulating BMI1 expression by enhanced miR-200c expression. 87 These results provide potential therapeutic agents for HCC.…”

BMI-1 activates hepatic stellate cells to promote EMT of colorectal cancer cells

“…In the liver microenvironment, HSC-derived CAFs are the main tumor-interacting population and play a vital role in cancer cell metastasis (Zhao et ). We previously reported that BMI-1 was abnormally high expressed in CRLM and inhibition of BMI-1 in CRC cells dramatically reduced LM in vivo (Xu et al 2021). The normal liver cells were BMI-1 negative, we observed that BMI-1 positive liver cells were common in CRLM samples from humans and mice.…”

“…BMI-1 regulates self-renewal of stem cell and participate in carcinogenesis of human cancers, including CRC(Jiang et al 2009;Tateishi et al 2006;Gil et al 2005). We have previously reported that BMI-1 was overexpressed in CRLM and contributes to the LM by regulating epithelial-mesenchymal transition (EMT) of CRC cells in vitro and in vivo(Xu et al 2021). Interestingly, we observed BMI-1 positive staining in liver cells both in human and mice liver specimens of CRLM.…”

Up-regulated Circular RNAs in Colorectal Cancer: New Entities for Therapy and Tools for Identification of Therapeutic Targets

“…The latter acted as a transcriptional repressor and is a member of the polycomb group of proteins which modify chromatin structure (41). BMI-1 mediates EMT, liver metastasis and drug resistance (42,43).…”