title: Berberine reverses epithelial-to-mesenchymal transition and inhibits metastasis and tumor-induced angiogenesis in human cervical cancer cells.
abstract: Metastasis is the most common cause of cancer-related death in patients, and epithelial-to-mesenchymal transition (EMT) is essential for cancer metastasis, which is a multistep complicated process that includes local invasion, intravasation, extravasation, and proliferation at distant sites. When cancer cells metastasize, angiogenesis is also required for metastatic dissemination, given that an increase in vascular density will allow easier access of tumor cells to circulation, and represents a rational target for therapeutic intervention. Berberine has several anti-inflammation and anticancer biologic effects. In this study, we provided molecular evidence that is associated with the antimetastatic effect of berberine by showing a nearly complete inhibition on invasion (P < 0.001) of highly metastatic SiHa cells via reduced transcriptional activities of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Berberine reversed transforming growth factor-β1-induced EMT and caused upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and snail-1. Selective snail-1 inhibition by snail-1-specific small interfering RNA also showed increased E-cadherin expression in SiHa cells. Berberine also reduced tumor-induced angiogenesis in vitro and in vivo. Importantly, an in vivo BALB/c nude mice xenograft model and tail vein injection model showed that berberine treatment reduced tumor growth and lung metastasis by oral gavage, respectively. Taken together, these findings suggested that berberine could reduce metastasis and angiogenesis of cervical cancer cells, thereby constituting an adjuvant treatment of metastasis control.
authors.affiliation: Institute and Department of Food Science, Central Taiwan University of Science and Technology, Taichung, Taiwan (S.-C.C.); Institute of Oral Science, School of Dentistry (C.-C.Y.), Institute of Biochemistry and Biotechnology (L.-S.H., M.-Y.S., P.-N.C.), and Institute of Medicine (K.-S.C.), Chung Shan Medical University, Taichung, Taiwan; Clinical Laboratory (M.-Y.S., P.-N.C.), Department of Dentistry (C.-C.Y.), and Department of Internal Medicine (K.-S.C.), Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Chu
authors.affiliation: Institute and Department of Food Science, Central Taiwan University of Science and Technology, Taichung, Taiwan (S.-C.C.); Institute of Oral Science, School of Dentistry (C.-C.Y.), Institute of Biochemistry and Biotechnology (L.-S.H., M.-Y.S., P.-N.C.), and Institute of Medicine (K.-S.C.), Chung Shan Medical University, Taichung, Taiwan; Clinical Laboratory (M.-Y.S., P.-N.C.), Department of Dentistry (C.-C.Y.), and Department of Internal Medicine (K.-S.C.), Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Institute and Department of Food Science, Central Taiwan University of Science and Technology, Taichung, Taiwan (S.-C.C.); Institute of Oral Science, School of Dentistry (C.-C.Y.), Institute of Biochemistry and Biotechnology (L.-S.H., M.-Y.S., P.-N.C.), and Institute of Medicine (K.-S.C.), Chung Shan Medical University, Taichung, Taiwan; Clinical Laboratory (M.-Y.S., P.-N.C.), Department of Dentistry (C.-C.Y.), and Department of Internal Medicine (K.-S.C.), Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Li-Sung
authors.initials: LS
authors.lastname: Hsu
authors.affiliation: Institute and Department of Food Science, Central Taiwan University of Science and Technology, Taichung, Taiwan (S.-C.C.); Institute of Oral Science, School of Dentistry (C.-C.Y.), Institute of Biochemistry and Biotechnology (L.-S.H., M.-Y.S., P.-N.C.), and Institute of Medicine (K.-S.C.), Chung Shan Medical University, Taichung, Taiwan; Clinical Laboratory (M.-Y.S., P.-N.C.), Department of Dentistry (C.-C.Y.), and Department of Internal Medicine (K.-S.C.), Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Kuo-Shuen
authors.initials: KS
authors.lastname: Chen
authors.affiliation: Institute and Department of Food Science, Central Taiwan University of Science and Technology, Taichung, Taiwan (S.-C.C.); Institute of Oral Science, School of Dentistry (C.-C.Y.), Institute of Biochemistry and Biotechnology (L.-S.H., M.-Y.S., P.-N.C.), and Institute of Medicine (K.-S.C.), Chung Shan Medical University, Taichung, Taiwan; Clinical Laboratory (M.-Y.S., P.-N.C.), Department of Dentistry (C.-C.Y.), and Department of Internal Medicine (K.-S.C.), Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Su
authors.affiliation: Institute and Department of Food Science, Central Taiwan University of Science and Technology, Taichung, Taiwan (S.-C.C.); Institute of Oral Science, School of Dentistry (C.-C.Y.), Institute of Biochemistry and Biotechnology (L.-S.H., M.-Y.S., P.-N.C.), and Institute of Medicine (K.-S.C.), Chung Shan Medical University, Taichung, Taiwan; Clinical Laboratory (M.-Y.S., P.-N.C.), Department of Dentistry (C.-C.Y.), and Department of Internal Medicine (K.-S.C.), Chung Shan Medical University Hospital, Taichung, Taiwan peini@csmu.edu.tw.
authors.forename: Pei-Ni
authors.initials: PN
authors.lastname: Chen
mesh_terms: D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002645:Chickens; D049033:Chorioallantoic Membrane; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism
chemical_list: D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D001599:Berberine; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2