microRNA-192 suppresses the expression of the farnesoid X receptor

Abstract

Farnesoid X receptor (FXR, NR1H4) plays an important role in the regulation of bile acid homeostasis in liver and intestine and may exert protective effects against certain forms of cancer such as colon carcinoma. However, the role of FXR in cell growth regulation, apoptosis, and carcinogenesis is still controversial. Similar to FXR, microRNA-192 (miR-192) is mainly expressed in the liver and colon and plays an important role in the pathogenesis of colon carcinoma. In this study, we investigated the extent to which FXR is regulated by miR-192. Two in silico-predicted binding sites for miR-192-3p within the NR1H4-3' untranslated region (UTR) were examined in vitro by luciferase reporter assays. Wild-type and mutated forms of the NR1H4-3'UTR were subcloned into a pmirGLO vector and cotransfected into Huh-7 cells with miR-192-3p. To study the effects of miR-192 on the expression of FXR, FXR target genes and cell proliferation, Huh-7 and Caco-2 cells were transfected with miR-192-5p and -3p mimics or antagomirs. In addition, the correlation between FXR and miR-192 expression was studied by linear regression analyses in colonic adenocarcinoma tissue from 27 patients. MiR-192-3p bound specifically to the NR1H4-3'UTR and significantly decreased luciferase activity. Transfection with miR-192 led to significant decreases in NR1H4 mRNA and protein levels as well as the mRNA levels of the FXR-inducible bile acid transporters OSTα-OSTβ and OATP1B3. Significant inverse correlations were detected in colonic adenocarcinoma between NR1H4 mRNA and miR-192-3p expression. In summary, microRNA-192 suppresses the expression of FXR and FXR target genes in vitro and in vivo.

Abiraterone induces SLCO1B3 expression in prostate cancer via microRNA-579-3p

“…In a study evaluating membrane drug transporters and miRNA gene expression changes mediated by rifampin treatment in hepatocytes, SLCO1B3 expression was reduced after rifampin treatment and negatively correlated with rifampin-induced hsa-miR-92a expression 18 . In addition, hsa-miR-192 was found to inhibit FXR, a known regulator of SLCO1B3 , which in turn, suppressed SLCO1B3 expression 19 , 41 .…”

“…Though little research has involved miRNA in the direct regulation of SLCO1B3 in prostate cancer, SLCO1B3 was found to be negatively correlated with rifampin-induced miRNA expression in hepatocytes 18 . In addition, FXR and its target genes including SLCO1B3 are regulated by hsa-miR-192, also in hepatocytes 19 . More broadly, miRNA involvement in prostate cancer initiation, proliferation, progression, and therapeutic resistance has been relatively well described, with thousands of relevant miRNA species characterized.…”

Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis

“…Based on these observations, we propose a model in which an event initiated in tumor cells activates Wnt signaling at the early phase of colorectal tumorigenesis, thus elevating the levels of nuclear β-catenin, forming β-catenin/FXR complex and subsequently impairing the tumor-suppressor effect of FXR. Furthermore, due to DNA hypermethylation 30 , miRNA regulation 58 , or transcription factor regulation 59 , loss of FXR enhances the β-catenin/FXR complex and leads to persistent activation of Wnt signaling to further promote tumorigenesis (Supplementary Fig. 10).…”

Oxysterols and Gastrointestinal Cancers Around the Clock

“…The observed downregulation of FXR expression is due to increased methylation of FXR promotor by the loss of APC function, which was confirmed in CRC cell lines, animal models and colonic tumors from patients (174, 188, 189). However, FXR is also downregulated by intestinal inflammation, western diet, and microRNA (187, 190). The current hypothesis is that the decreased FXR regulation in combination with Western diet and hence higher levels of secondary bile acids results in pro-tumorigenic colon environment leading to the development of colon cancer.…”