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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-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.

SUBMITTER: Xu Z

PROVIDER: S-EPMC8148062 | biostudies-literature |

REPOSITORIES: biostudies-literature

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