title: The effect and mechanism of bufalin on regulating hepatocellular carcinoma cell invasion and metastasis via Wnt/β-catenin signaling pathway.
abstract: Hepatocellular carcinoma (HCC) is a highly malignant tumor with an extremely poor prognosis. Our preliminary study indicated that bufalin could restrain the proliferation of human hepatoma BEL-7402 cells in a time- and dose-dependent manner. In the present study, the colony formation assay, the Transwell invasion assay, the western blot analysis and the immunofluorescence method were respectively used to investigate the effect and mechanism of bufalin against HCC cell invasion and metastasis. We found that: i) bufalin had significant inhibitory effect on the cell proliferation of BEL-7402 cells; ii) bufalin markedly inhibited the migration and invasion of BEL-7402 cells; iii) bufalin could suppress the phosphorylation of GSK-3β Ser9 site in BEL-7402 cells, decrease the expression of β-catenin, cyclin D1, metalloproteinases-7 (MMP-7) and cyclooxygenase-2 (COX-2) in the cytoplasm, and increase the expression of E-cadherin and β-catenin on the cell membrane; and iv) the expression of α-fetoprotein significantly decreased and the expression of albumin increased in BEL-7402 cells after bufalin was used. Our results indicate that: i) bufalin can regulate the expression of associated factors in Wnt/β-catenin signaling pathway of BEL-7402 cells through suppressing the phosphorylation of GSK-3β Ser9 site; ii) bufalin can strengthen intercellular E-cadherin/β-catenin complex to control epithelial-mesenchymal transition; and iii) bufalin can reverse the malignant phenotype and promote the differentiation and maturation by regulating the AFP and ALB expression in BEL-7402 cells. These are very important mechanisms of bufalin on the inhibition of the invasion and metastasis of HCC cells.
authors.affiliation: Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Ji Qin
authors.initials: JQ
authors.lastname: Gai
authors.affiliation: Department of Pathology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Jian Min
authors.initials: JM
authors.lastname: Qin
authors.affiliation: Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Kang
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ni
mesh_terms: D002018:Bufanolides / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D002018:Bufanolides; D009363:Neoplasm Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C022777:bufalin