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Updated: Apr 18, 2026
Ileectomy-induced Bile Overaccumulation in Mouse Intestine
Published on: August 21, 2017
MiR-22-silenced cyclin A expression in colon and liver cancer cells is regulated by bile acid receptor
Fan Yang1, Ying Hu2, Hui-Xin Liu2
1From 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.
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.
Insights
Bile acids activate the farnesoid X receptor (FXR) to increase microRNA-22 (miR-22) levels, which then suppresses cyclin A2 (CCNA2) in liver and colon cells, offering a protective pathway.
Area of Science:
- Gastroenterology
- Molecular Biology
- Oncology
Background:
- MicroRNA-22 (miR-22) is a known tumor suppressor.
- The regulation and downstream targets of miR-22 in gastrointestinal cells require further elucidation.
Purpose of the Study:
- To investigate the regulation of miR-22 by bile acids and the farnesoid X receptor (FXR).
- To identify novel downstream targets of miR-22 in liver and colon cancer cells.
Main Methods:
- Luciferase reporter assays to confirm FXR binding to the miR-22 promoter.
- Quantitative real-time PCR and Western blotting to measure miR-22 and cyclin A2 (CCNA2) expression.
- Studies in FXR knockout (KO) mice and human cancer cell lines.
Main Results:
- FXR directly binds to the miR-22 promoter, inducing miR-22 expression in a dose- and time-dependent manner, particularly with chenodeoxycholic acid.
- CCNA2 is identified as a novel, conserved miR-22 target, with miR-22 directly inhibiting its translation.
- FXR activation, miR-22 induction, and CCNA2 suppression were shown to inhibit cell proliferation and correlate with inverse expression in human cancers.
Conclusions:
- Bile acid-activated FXR stimulates miR-22 expression, which in turn silences CCNA2.
- This pathway represents a novel mechanism for FXR's tumor-suppressive role in the gastrointestinal tract.
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