title: MiR-22-silenced cyclin A expression in colon and liver cancer cells is regulated by bile acid receptor.
abstract: Because of the significant tumor-suppressive role of microRNA-22 (miR-22), the current study was designed to understand the regulation of miR-22 and to identify additional downstream miR-22 targets in liver and colon cells. The data showed that miR-22 was transcriptionally regulated by bile acid receptor farnesoid X receptor (FXR) through direct binding to an invert repeat 1 motif located at -1012 to -1025 bp upstream from miR-22. Among the studied primary and secondary bile acids, chenodeoxycholic acid, which has the highest binding affinity to FXR, induced miR-22 level in both Huh7 liver and HCT116 colon cells in a dose- and time-dependent manner. In addition, cyclin A2 (CCNA2) was identified as a miR-22 novel target in liver and colon cancer cells. The sequence of miR-22, which is conserved in mice, rats, humans, and other mammalians, aligns with the sequence of 3'-UTR of CCNA2. Chenodeoxycholic acid treatment and miR-22 mimics reduced CCNA2 protein and increased the number of G0/G1 Huh7 and HCT116 cells. In FXR KO mice, reduction of miR-22 was accompanied by elevated hepatic and ileal CCNA2 protein, as well as an increased number of hepatic and colonic Ki-67-positive cells. In humans, the expression levels of miR-22 and CCNA2 are inversely correlated in liver and colon cancers. Taken together, our data showed that bile acid-activated FXR stimulates miR-22-silenced CCNA2, a novel pathway for FXR to exert its protective effect in the gastrointestinal tract.
authors.affiliation: From the Department of Pathology and Laboratory Medicine, the University of California at Davis Medical Center, Sacramento, California 95817 and the Institute of Chinese Material Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: From the Department of Pathology and Laboratory Medicine, the University of California at Davis Medical Center, Sacramento, California 95817 and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: From the Department of Pathology and Laboratory Medicine, the University of California at Davis Medical Center, Sacramento, California 95817 and.
authors.forename: Hui-Xin
authors.initials: HX
authors.lastname: Liu
authors.affiliation: From the Department of Pathology and Laboratory Medicine, the University of California at Davis Medical Center, Sacramento, California 95817 and the Institute of Chinese Material Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China yjywan@ucdavis.edu.
authors.forename: Yu-Jui Yvonne
authors.initials: YJ
authors.lastname: Wan
mesh_terms: D001647:Bile Acids and Salts / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D056751:Cyclin A2 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D056751:Cyclin A2; D035683:MicroRNAs; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C503721:CCNA2 protein, human; C548375:MIRN22 microRNA, human
keywords: Bile Acid; Colon Cancer; Liver Cancer; MicroRNA (miRNA); Nuclear Receptor