Published online Jun 21, 2023. doi: 10.3748/wjg.v29.i23.3606
Peer-review started: February 1, 2023
First decision: February 12, 2023
Revised: February 25, 2023
Accepted: May 4, 2023
Article in press: May 4, 2023
Published online: June 21, 2023
Processing time: 135 Days and 3.3 Hours
Hepatic stellate cells (HSCs) are an important component of liver tissue and are a major source of cancer-associated fibroblasts. Cancer cells can activate HSCs, and in turn activated HSCs (aHSCs) promote tumor growth and metastasis. However, the mechanisms by which HSCs interact with colorectal cancer (CRC) cells to promote liver metastases (LM) are largely unknown.
We previously discovered that the expression of BMI-1 was abnormally high in LM of CRC. We speculated that BMI-1 plays an important role in the interaction between HSCs and CRC cells.
To examine the role of BMI-1 in HSC activation, and investigate the potential mechanisms of BMI-1 in the interaction between HSCs and CRC cells.
The expression of BMI-1 in liver tissue of patients with CRC liver metastasis (CRLM) was determined by immunohistochemistry analysis. We established a mouse LM model to assess the expression of BMI-1 during CRLM. We used lentiviral vectors to overexpress BMI-1 in LX2 HSCs (LX2 BMI-1) and evaluated the molecular markers of aHSCs. The proliferation and mobility of CRC cells in LX2 BMI-1 conditioned medium (CM) was detected. The epithelial-mesenchymal transition (EMT) and transforming growth factor beta (TGF-β)/SMAD pathway in CRC cells treated with LX2 BMI-1 CM were investigated by Western blot analysis and quantitative polymerase chain reaction. A mouse xenograft model was established to investigate the effects of co-implantation of LX2 BMI-1 and CRC cells on tumor growth, and the EMT phenotype of CRC.
BMI-1 expression was upregulated in liver cells during CRLM. Overexpression of BMI-1 induced the activation of LX2 HSCs. CRC cells cultured in LX2 BMI-1 CM showed higher proliferation, migration, and EMT ability compared with cells cultured in NC CM. LX2 BMI-1 CM induced activation of the TGF-β/SMAD pathway in CRC cells, and the TGF-βR inhibitor SB-505124 diminished the effect of BMI-1 CM. In addition, LX2 BMI-1 HSCs promoted CRC tumor growth and EMT in the mouse model.
BMI-1 aHSCs promoted the proliferation and migration of CRC partly via the TGF-β/SMAD pathway.
Targeting BMI-1 in liver tissues may have potential therapeutic implications for the treatment of CRLM.