Bile Acids Regulate Expression of a Tumor Suppressive MicroRNA

The miRNA miR-22 has long been known for its ability to suppress cancer, but how this action was regulated was not well understood.

Investigators at the University of California, Davis (USA) recently published a study that had been designed to understand the regulation of miR-22 and to identify additional downstream miR-22 targets in liver and colon cells. To this end they worked with a population of mice that had been genetically engineered to lack the gene for the bile acid receptor, farnesoid x receptor (FXR), which moderates bile acid and cholesterol metabolism. Mice lacking FXR spontaneously develop liver cancer. The investigators also examined the expression of miR-22 in human liver cancer and colon cancer specimens.

Results published in the March 6, 2015, issue of the Journal of Biological Chemistry revealed that miR-22 was transcriptionally regulated by FXR through direct binding to an invert repeat one motif located from 1,012 to 1,025 base pairs 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 levels in both Huh7 liver and HCT116 colon cells in a dose- and time-dependent manner.

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, was found to align 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 mice genetically engineered to lack FXR, 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 were found to be inversely correlated in liver and colon cancers.

"There are quite a few molecules present in the gastrointestinal (GI) tract that regulate miR-22," said senior author Dr. Yu-Jui Yvonne Wan, professor of pathology and laboratory medicine at the University of California, Davis. "If so many chemicals in the GI tract can regulate miR-22, it must be physiologically significant. We needed to better understand the molecules that regulate miR-22 in cancer, as well as the pathways miR-22 controls."

The investigators also found that miR-22 was activated by vitamin D3, which can reduce the toxicity of hydrophobic bile acids. "People who are obese, or eating a high-fat Western diet, tend to have dysregulated bile acid synthesis," said Dr. Wan. "When that happens, FXR can be inactivated, potentially decreasing the level of miR-22, increasing the expression of cyclin A2 and disrupting the cell cycle. So this pathway may play a role in Western diet-associated carcinogenesis. I am not so sure miR-22 is all good. We do not know what it will target in normal cells. Our next step is to identify more miR-22 effects."

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