Berberine inhibits colorectal liver metastasis via modulation of TGF-β in a cecum transplant mouse model

Abstract

Abstract Background Hepatic metastasis is the primary cause of colorectal cancer (CRC)-induced death. Our previous results showed the anti-metastatic effects of Coptidis rhizoma using in vitro model. Aim The present study aimed to investigate whether berberine, the main active compound of C. rhizoma, inhibits colon–liver metastasis in an animal model, and to elucidate the underlying mechanisms. Methods Murine colon carcinoma (CT26) tumor tissue was implanted into the cecum of balb/c mice with/without oral administration of berberine (100 mg/kg) for 21 days, after which liver metastasis was evaluated. In addition, the pharmacological actions of berberine were explored using 5-fluorouracil-resistant human colon cancer cells (HCT116/R). Result The administration of berberine significantly decreased the number of tumor nodules in the liver, while significant activation of E-cadherin (an epithelial marker), and suppression of vimentin, Snail and TGF-β (mesenchymal markers) were observed in primary colon tumor tissues. Berberine treatment also notably lowered the levels of inflammatory cytokines (TGF-β, TNF- α, IL-6 and IL-1β) in the blood. In HCT116/R cells, berberine significantly inhibited migration and invasion and modulated the expression of TGF-β and representative molecules related to its pathway. The results obtained with a TGF-β inhibitor (SB431542) and a TGF-β siRNA, strongly suggest that the mechanism of action of berberine is linked to TGF-β signaling. Conclusion In conclusion, berberine evidently possess an anti-colon–liver metastatic effect, and its underlying mechanisms involve the inhibition of epithelial–mesenchymal transition (EMT) through the TGF-β signaling pathway. Thus, we cautiously propose the pharmacological potential of berberine in drug research studies targeting hepatic metastasis from CRC.

Keywords

• Colorectal cancer
• Metastasis
• 5-Fluorouracil
• EMT
• Berberine
• TGF-β