MicroRNA-145 Post-transcriptionally Regulates the Expression and Function of P-glycoprotein in Intestinal Epithelial Cells

Abstract

P-glycoprotein (P-gp/MDR1) is a multispecific efflux transporter regulating the pharmacokinetics of various drugs. Although P-gp expression in the small intestine is elevated after liver ischemiareperfusion (I/R) injury, the regulatory mechanism remains to be clarified. MicroRNAs (miRNAs) play an important role in the posttranscriptional regulation of the expression of drug transporters. Here, we investigated the intestinal expression profile of miRNAs after liver I/R and the role of miRNAs in the post-transcriptional regulation of P-gp in intestinal epithelial cells. Microarray analysis showed that microRNA-145 (miR-145) level was decreased in the small intestine of I/R rats. This downregulation of miR-145 was further confirmed by real-time polymerase chain reaction. In silico analysis revealed that 39-untranslated regions (UTRs) of rat Mdr1a, mouse Mdr1a, and human MDR1 mRNA retain binding sites for miR-145. Luciferase assays using MDR1 39-UTR reporter plasmid in HEK293 cells showed that luciferase activity was decreased by the overexpression of miR-145, and the deletion of miR-145 binding site within MDR1 39-UTR abolished this decreased luciferase activity. The downregulation of miR-145 in Caco-2 cells, an epithelial cell line derived from human colon, increased P-gp expression and efflux activity of rhodamine 123, but not MDR1 mRNA level. These findings demonstrated that miR-145 negatively regulates the expression and function of P-gp through the repression of mRNA by direct interaction on the 39-UTR of MDR1 mRNA. In addition, the downregulation of miR-145 should significantly contribute to the elevated intestinal P-gp expression after liver I/R. Our results provide new insight into the post-transcriptional regulation of intestinal P-gp.

MicroRNA-298 Reverses Multidrug Resistance to Antiepileptic Drugs by Suppressing MDR1/P-gp Expression in vitro

“…According to several recent studies, miRNAs modulate MDR by altering the expression of ABC transporters, such as BCRP and P-gp, in tumor cells (Haenisch et al, 2014). For example, miR-129 and miR-145 inhibit P-gp expression and sensitize human cancer cells to chemotherapy drugs by directly targeting the 3′-UTR of MDR1 (Ikemura et al, 2013; Lu et al, 2017). Additionally, the overexpression of miR-506 and miR-138 have been reported to indirectly downregulate P-gp expression by regulating different signaling pathways (Requenez-Contreras et al, 2017; Zhou et al, 2017).…”

MDR1 in immunity: friend or foe?

“…36,37 MDR1 is also regulated at RNA level by micro RNAs (miR) such as miR-145, miR-27a and miR-331-5p that bind directly the 3ʹUTR of ABCB1 mRNA to decrease MDR1 expression. 38,39 Some other miR (miR-137) indirectly decrease MDR1 expression by targeting the YB-1 transcription factor that upregulates MDR1 expression by fixation on ABCB1 promoter. 40,41 …”

MDR1 will play a key role in pharmacokinetic changes under hypoxia at high altitude and its potential regulatory networks

“…For instance, overexpression of miR-451 (Kovalchuk et al, 2008), miR-145 (Ikemura et al, 2013), miR-298 (Bao et al, 2012) and miR-27a (Zhao et al, 2011;Zhang et al, 2010) are found to inhibit the MDR1 gene expression, but miR-331-5p (Feng et al, 2011) increase MDR1 expression by direct interaction with the 3 0 -UTR of the MDR1 mRNA region. Several miRs have been described as DOI: 10.3109/03602532.2015.1007012 Role of MDR1 in pharmacokinetic changes under hypoxia 5 Drug Metabolism Reviews Downloaded from informahealthcare.com by University of Calgary on 02/03/15 ''possibly indirect regulators'' of MDR1, for instance, miR-451, miR-27a, miR-21 (Seca et al, 2013), miR-130a (Yang et al, 2012) and miR-let-7 (Boyerinas et al, 2012), by targeting other mRNAs, which code for intermediate proteins or transcription factors involved in MDR1 gene activation ( Figure 5).…”