Abstract
Bile acids are implicated in colorectal carcinogenesis as evidenced by epidemiological and experimental studies. We examined whether bile acids stimulate cellular invasion of human colorectal and dog kidney epithelial cells at different stages of tumor progression. Colon PC/AA/C1, PCmsrc, and HCT-8/E11 cells and kidney MDCKT23 cells were seeded on top of collagen type I gels and invasive cells were counted after 24 h incubation. Activation of the Rac1 and RhoA small GTPases was investigated by pull-down assays. Haptotaxis was analysed with modified Boyden chambers. Lithocholic acid, chenodeoxycholic acid, cholic acid and deoxycholic acid stimulated cellular invasion of SRC- and RhoA-transformed PCmsrc and MDCKT23-RhoAV14 cells, and of HCT-8/E11 cells originating from a sporadic tumor, but were ineffective in premalignant PC/AA/C1 and MDCKT23 cells. Bile acid-stimulated invasion occurred through stimulation of haptotaxis and was dependent on the RhoA/Rho-kinase pathway and signaling cascades using protein kinase C, mitogen-activated protein kinase, and cyclooxygenase-2. Accordingly, BA-induced invasion was associated with activation of the Rac1 and RhoA GTPases and expression of the farnesoid X receptor. We conclude that bile acids stimulate invasion and haptotaxis in colorectal cancer cells via several cancer invasion signaling pathways.
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Acknowledgements
We thank L Baeke, R Colman, G Desmet, G De Bruyne and A Verspeelt for technical assistance, Dr F André and Dr T Boterberg (Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium) and Dr V Rigot (Unité de Biologie Cellulaire, Université Catholique de Louvain, Brussels, Belgium) for helpful suggestions, and Dr J-C Lissitzky (Laboratoire de Biochimie Cellulaire, CNRS, Marseille, France) for providing the antibody against αV integrin.
This work was supported by the ‘FWO-Vlaanderen’ (Brussels, Belgium), the ‘Sportvereniging tegen Kanker’ (Brussels, Belgium), the ‘ASLK/VIVA-verzekeringen’ (Brussels, Belgium), the ‘G.O.A. from the Vlaamse Gemeenschap’ (Brussels, Belgium), INSERM and ARC (France) and the ‘Deutsche Krebshilfe e.V.’ (Bonn, Germany). Ph. Debruyne is a Research Assistant with the ‘Bijzonder Onderzoeksfonds Universiteit Gent’ (Ghent, Belgium).
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Debruyne, P., Bruyneel, E., Karaguni, IM. et al. Bile acids stimulate invasion and haptotaxis in human colorectal cancer cells through activation of multiple oncogenic signaling pathways. Oncogene 21, 6740–6750 (2002). https://doi.org/10.1038/sj.onc.1205729
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DOI: https://doi.org/10.1038/sj.onc.1205729
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