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

Abstract

Activated hepatic stellate cells (aHSCs) are the major source of cancer-associated fibroblasts (CAFs) in the liver. Though the crosstalk between aHSCs and colorectal cancer (CRC) cells supports liver metastasis (LM), the mechanisms remain largely unknown. Here, we investigated BMI-1, a polycomb-group protein family member, which is high-expressed in LM, in hepatic stellate cells (HSCs) activation and interacting with CRC cells while promoting colorectal cancer liver metastasis (CRLM). We found the positivity of BMI-1 expression in the liver of CRLM patients was 77.8%, and the expression level of BMI-1 continued to increase during CRLM in mice. We overexpressed BMI-1 in HSCs (LX2) by lentivirus infection, and HSCs were activated, accompanied by increased expression levels of α-SMA, Fibronectin, TGF-β1, MMPs, and IL-6. CRC cells (HCT116 and DLD1) were cultured in HSCs-conditioned medium (LX2 NC CM or LX2 BMI-1 CM), and CRC cells cultured in BMI-1 CM exhibited enhanced proliferation and migration ability, and EMT phenotype with activation of TGF-β/SMAD pathway. Besides, a TFG-βR inhibitor SB-505124 largely diminished the effect of the BMI-1 CM on Smad2/3 phosphorylation in CRC cells. A mouse subcutaneous xenotransplantation tumor model was established by co-implantation of HSCs (LX2 NC or LX2 BMI-1) and CRC cells, andBMI-1 overexpressed LX2 HSCs promoted tumor growth and epithelial-mesenchymal transition (EMT) phenotype in vivo. In conclusion, BMI-1 activates HSCs to promote the EMT of CRC cells partially through the TGF-β/SMAD pathway. These findings demonstrate BMI-1 activated HSCs might be a new target in CRC therapy.