HuR-mediated posttranscriptional regulation of p21 is involved in the effect of Glycyrrhiza uralensis licorice aqueous extract on polyamine-depleted intestinal crypt cells proliferation

Glycyrrhiza uralensis licorice has long been used worldwide as a food additive and herbal medicine. It possesses a remarkable healing action on gastrointestinal ulcers. The present study was carried out to assess the effect of licorice on intestinal crypt cell proliferation and to investigate the corresponding molecular mechanism. Considering the role of crypt stem cells in intestinal mucosa repair, a well-established cytostatic cellular model, polyamine-depleted IEC-6 cells, was utilized to evaluate the effect of aqueous licorice on the proliferation of intestinal crypt cells. The growth inhibition of IEC-6 cells caused by alpha-difluoromethylornithine could be significantly reversed by concomitant treatment with 40 μg/ml and 80 μg/ml licorice aqueous extract. In particular, the restoration of cell cycle progression was accompanied by a decrease in p21 mRNA level and cytoplasmic accumulation of the RNA-binding protein HuR, which was shown to be involved in the destabilization of p21 mRNA. Using a biotin pull-down assay and a luciferase assay, it was found that licorice-modulated p21 mRNA expression was achieved by HuR-targeted AU-rich and U-rich elements that resided in the 3′ untranslated region of p21 mRNA. These results demonstrate that licorice can exert its action on stimulating the growth of intestinal crypt cells by regulating p21 mRNA level at the posttranscriptional level by HuR.