Regulation of ABCG2 Expression at the 3′ Untranslated Region of Its mRNA through Modulation of Transcript Stability and Protein Translation by a Putative MicroRNA in the S1 Colon Cancer Cell Line

To, Kenneth K.W.; Zhan, Zhirong; Litman, Thomas; Bates, Susan E.

doi:10.1128/mcb.00331-08

Cited by 148 publications

(151 citation statements)

References 51 publications

(62 reference statements)

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“…Recent studies have shown that other proteins involved in drug metabolism (Tsuchiya et al, 2006;Takagi et al, 2008;To et al, 2008;Pan et al, 2009) are also subject to miRNA regulation. Our results, taken together with those findings, suggest a complex regulatory mechanism for cytochromes P450 by miRNAs.…”

Section: Discussionmentioning

confidence: 99%

In Silico and In Vitro Identification of MicroRNAs That Regulate Hepatic Nuclear Factor 4α Expression

Ramamoorthy¹,

Li²,

Gaedigk³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Hepatic nuclear factor 4␣ (HNF4A) is a nuclear transcription factor that regulates the expression of many genes involved in drug disposition. To identify additional molecular mechanisms that regulate HNF4A, we identified microRNAs (miRNAs) that target HNF4A expression. In silico analyses suggested that HNF4A is targeted by many miRNAs. We conducted in vitro studies to validate several of these predictions. With use of an HNF4A 3-untranslated region (UTR) luciferase reporter assay, five of six miRNAs tested significantly downregulated (ϳ20-40%) the luciferase activity. In HepG2 cells, miR-34a and miR-449a also down-regulated the expression of both the HNF4A protein and an HNF4A target gene, PXR (ϳ30-40%). This regulation appeared without reduction in HNF4A mRNA expression, suggesting that they must be blocking HNF4A translation. Using additional bioinformatic algorithms, we identified polymorphisms that are predicted to alter the miRNA targeting of HNF4A. Luciferase assays indicated that miR-34a and miR-449a were less effective in regulating a variant (rs11574744) than the wild-type HNF4A 3-UTR. In vivo, subjects with the variant HNF4A had lower CYP2D6 enzyme activity, although this result was not statistically significant (p ‫؍‬ 0.16). In conclusion, our findings demonstrate strong evidence for a role of miRNAs in the regulation of HNF4A.

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Section: Discussionmentioning

confidence: 99%

In Silico and In Vitro Identification of MicroRNAs That Regulate Hepatic Nuclear Factor 4α Expression

Ramamoorthy¹,

Li²,

Gaedigk³

et al. 2012

Drug Metab Dispos

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“…Kenneth et al 58 have shown that ABCG2 mRNA adopts a longer 3 0 UTR in the parental S1 colon cancer cell line than its mitoxantrone-resistant counterpart S1MI80. HsamiR-519c decreases ABCG2 mRNA and protein levels by acting through a putative binding site located within the longer 3 0 UTR in parental cells, but the binding site for this miRNA is lost in the shorter 3 0 UTR in the resistant cells, therefore mRNA degradation and/or repression on protein translation is relieved, which contributes to the overexpression of ABCG2.…”

Section: Colon Cancermentioning

confidence: 99%

MicroRNA and drug resistance

2010

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Chemotherapy is the preferred treatment for malignancies. However, a successful long-term use of chemotherapy is often prevented by the development of drug resistance. Many mechanisms such as gene mutation, DNA methylation and histone modification have important roles in the resistance of cancer cells to chemotherapeutic agents. Climent suggested miR-125b was involved in the development of drug resistance by microRNA (miRNA) dysregulation. miRNAs are endogenously expressed small non-coding RNAs, which are evolutionarily conserved and function as regulators of gene expression. Much effort has been exerted in analyzing the role of miRNAs in the development of drug resistance in a variety of malignancies. Several research groups have shown that the expressions of miRNAs in chemoresistant cancer cells and their parental chemosensitive ones are different. The molecular targets and mechanisms of chemosensitivity and chemoresistance are also elucidated. This article reviews the functions of miRNAs in the development of drug resistance.

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“…They usually act through base pairing to a partially complementary segment within the 3ЈUTR transcript of a target gene, which causes translation inhibition and/or mRNA cleavage and leads to a reduced expression of the target gene. With the understanding of miRNA function, there is increased interest in delineating the role of miRNAs in posttranscriptional regulation of drug-metabolizing enzymes, drug transporters, and nuclear receptors (Tsuchiya et al, 2006;Yu, 2007;Kovalchuk et al, 2008;Liao et al, 2008;Takagi et al, 2008;To et al, 2008;Zhu et al, 2008;Ji et al, 2009;Pan et al, 2009), which may not only provide insight into miRNA biological function but also advance the understanding of the integrated response of cells to xenobiotic drugs. Of note, Takagi et al (2008) has shown that CYP3A4 can be indirectly regulated by miRNA via microRNA-148a (miR-148a)-controlled regulation of PXR.…”

mentioning

confidence: 99%

MicroRNAs Regulate CYP3A4 Expression via Direct and Indirect Targeting

Pan¹,

Gao²,

Jilek³

2009

Drug Metab Dispos

236

189

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ABSTRACT:CYP3A4 metabolizes many drugs on the market. Although transcriptional regulation of CYP3A4 is known to be tightly controlled by some nuclear receptors (NR) including vitamin D receptor (VDR/ NR1I1), posttranscriptional regulation of CYP3A4 remains elusive. In this study, we show that noncoding microRNAs (miRNAs) may control posttranscriptional and transcriptional regulation of CYP3A4 by directly targeting the 3-untranslated region (3UTR) of CYP3A4 and indirectly targeting the 3UTR of VDR, respectively. Luciferase reporter assays showed that CYP3A4 3UTR-luciferase activity was significantly decreased in human embryonic kidney 293 cells transfected with plasmid that expressed microRNA-27b (miR-27b) or mouse microRNA-298 (mmu-miR-298), whereas the activity was unchanged in cells transfected with plasmid that expressed microRNA-122a or microRNA-328. Disruption of the corresponding miRNA response element (MRE) within CYP3A4 3UTR led to a 2-to 3-fold increase in luciferase activity. Immunoblot analyses indicated that CYP3A4 protein was down-regulated over 30% by miR-27b and mmu-miR-298 in LS-180 and PANC1 cells. The decrease in CYP3A4 protein expression was associated with significantly decreased CYP3A4 mRNA levels, as determined by quantitative real-time PCR (qPCR) analyses. Likewise, interactions of miR-27b or mmu-miR-298 with VDR 3UTR were supported by luciferase reporter assays. The mmu-miR-298 MRE site is well conserved within the 3UTR of mouse, rat, and human VDR. Downregulation of VDR by the two miRNAs was supported by immunoblot and qPCR analyses. Furthermore, overexpression of miR-27b or mmu-miR-298 in PANC1 cells led to a lower sensitivity to cyclophosphamide. Together, these findings suggest that CYP3A4 gene expression may be regulated by miRNAs at both the transcriptional and posttranscriptional level.

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Regulation of ABCG2 Expression at the 3′ Untranslated Region of Its mRNA through Modulation of Transcript Stability and Protein Translation by a Putative MicroRNA in the S1 Colon Cancer Cell Line

Cited by 148 publications

References 51 publications

In Silico and In Vitro Identification of MicroRNAs That Regulate Hepatic Nuclear Factor 4α Expression

In Silico and In Vitro Identification of MicroRNAs That Regulate Hepatic Nuclear Factor 4α Expression

MicroRNA and drug resistance

MicroRNAs Regulate CYP3A4 Expression via Direct and Indirect Targeting

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