Micro<scp>RNA</scp>s and their relevance to <scp>ABC</scp> transporters

Haenisch, Sierk; Werk, Anneke Nina; Cascorbi, Ingolf

doi:10.1111/bcp.12251

Cited by 78 publications

(54 citation statements)

References 66 publications

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“…To evaluate the expression of selected miRNAs in preterm placentas with chorioaminionitis, we performed qPCR analysis of miRNAs selected on the basis of their regulatory actions on P-gp ( miR-145, miR-200c, miR-331-5p and miR-451 ) [44]. Placental expression of miR-331-5p (p=0.003) was significantly increased in the PTDC compared to the PTD group (Fig.…”

Section: Resultsmentioning

confidence: 99%

Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta

Império

Bloise

Javam³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The ATP-binding cassette (ABC) transporters mediate drug biodisposition and immunological responses in the placental barrier. In vitro infective challenges alter expression of specific placental ABC transporters. We hypothesized that chorioamnionitis induces a distinct pattern of ABC transporter expression. Methods: Gene expression of 50 ABC transporters was assessed using TaqMan® Human ABC Transporter Array, in preterm human placentas without (PTD; n=6) or with histological chorioamnionitis (PTDC; n=6). Validation was performed using qPCR, immunohistochemistry and Western blot. MicroRNAs known to regulate P-glycoprotein (P-gp) were examined by qPCR. Results: Up-regulation of ABCB9, ABCC2 and ABCF2 mRNA was detected in chorioamnionitis (p<0.05), whereas placental ABCB1 (P-gp; p=0.051) and ABCG2 (breast cancer resistance protein-BCRP) mRNA levels (p=0.055) approached near significant up-regulation. In most cases, the magnitude of the effect significantly correlated to the severity of inflammation. Upon validation, increased placental ABCB1 and ABCG2 mRNA levels (p<0.05) were observed. At the level of immunohistochemistry, while BCRP was increased (p<0.05), P-gp staining intensity was significantly decreased (p<0.05) in PTDC. miR-331-5p, involved in P-gp suppression, was upregulated in PTDC (p<0.01) and correlated to the grade of chorioamnionitis (p<0.01). Conclusions: Alterations in the expression of ABC transporters will likely lead to modified transport of clinically relevant compounds at the inflamed placenta. A better understanding of the potential role of these transporters in the events surrounding PTD may also enable new strategies to be developed for prevention and treatment of PTD.

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Section: Resultsmentioning

confidence: 99%

Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta

Império

Bloise

Javam³

et al. 2018

Cell Physiol Biochem

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“…Often, these studies demonstrated that BCRP/ABCG2 expression is altered as consequence of treatment with certain drugs, e.g., by inducing a reduction of ABCG2 promoter DNA methylation 45 or altering miRNA expression (reviewed in Haenisch et al 46 ). Often, these studies demonstrated that BCRP/ABCG2 expression is altered as consequence of treatment with certain drugs, e.g., by inducing a reduction of ABCG2 promoter DNA methylation 45 or altering miRNA expression (reviewed in Haenisch et al 46 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma

Reustle

Fisel

Renner

et al. 2018

Intl Journal of Cancer

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The efflux transporter breast cancer resistance protein BCRP/ABCG2 is well-known for its contribution to multi-drug resistance in cancer. Its relevance in cancer biology independent from drug efflux remains largely elusive. Our study aimed at elucidating the biological relevance and regulatory mechanisms of BCRP/ABCG2 in clear cell renal cell carcinoma (ccRCC) and disease progression. Two independent ccRCC-cohorts [Cohort 1 (KIRC/TCGA): n = 453, Cohort 2: n = 64] were investigated to elucidate BCRP/ABCG2 mRNA and protein expression and their association with survival. The impact of BCRP/ABCG2 on response to sunitinib treatment was investigated in two independent sunitinib-treated ccRCC-cohorts based on mRNA levels. Moreover, underlying regulatory mechanisms for interindividual variability of BCRP/ABCG2 expression were systematically assessed. Owing to redundant functional properties, mRNA and protein expression of the multidrug resistance protein MDR1/ABCB1 were additionally evaluated in these cohorts. In independent ccRCC-cohorts, low BCRP/ABCG2 and MDR1/ABCB1 mRNA and protein expression were associated with severity (e.g., tumor stage) of ccRCC and poor cancer-specific survival. BCRP/ABCG2 and MDR1/ABCB1 mRNA expression were linked to decreased progression-free survival after sunitinib treatment. Germline and somatic variants influenced interindividual variability of BCRP/ABCG2 expression only moderately. miR-212-3p and miR-132-3p were identified to regulate BCRP/ABCG2 posttranscriptionally by interaction with the ABCG2 3'UTR as confirmed through reporter gene assays in RCC cell lines. In summary, BCRP/ABCG2 expression in ccRCC underlies considerable interindividual variability with impact on patient survival and response to sunitinib treatment. While germline or somatic genetic variants and DNA methylation cannot explain aberrant BCRP/ABCG2 expression, miR-212-3p and miR-132-3p were identified to contribute to posttranscriptional regulation of BCRP/ABCG2.

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“…Over 329 target genes of let‐7a‐5p have been identified in low‐throughput or high‐throughput miRNA targeting studies from the MiRTarBase miRNA Targets data set, but did not include ABCC2 . ABCC5 and ABCC10 are apparent targets but the localization and function of these transporters are not well understood in liver . Because a gene can be regulated by many different miRNAs depending on the cellular context, it is not surprising that ABCC2 expression in HepG2 cells and in human peripheral blood monocytic cells is regulated by miRNA‐379 .…”

Section: Discussionmentioning

confidence: 99%

Up‐regulation of miR‐let7a‐5p Leads to Decreased Expression of ABCC2 in Obstructive Cholestasis

et al. 2019

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Adenosine triphosphate–binding cassette subfamily C member 2 (ABCC2/Abcc2) is critically important to biliary excretion of many endobiotic and xenobiotic compounds, and is a major driving force for bile acid–independent bile flow. Abcc2 expression is reduced at the messenger RNA (mRNA) and protein levels in various forms of experimental cholestasis. In a microRNA (miRNA) screen of mouse liver after biliary obstruction, we found that miRNA let7a‐5p was significantly up‐regulated approximately 4‐fold. Similarly, ABCC2 mRNA was depleted and miRNA let7a‐5p was elevated over 4‐fold in livers of children with biliary atresia compared with normal livers. In silico analysis predicted that let7a‐5p would target the 3′ untranslated region (3′ UTR) of ABCC2/Abcc2 RNA. The objective of this study was to determine whether let7a‐5p contributes to the depletion of ABCC2/Abcc2 in cholestasis. To demonstrate the functional importance of miRNA let7a‐5p in regulating the expression of ABCC2, co‐transfection of a let7a‐5p mimic and an ABCC2‐3′ UTR luciferase construct into Huh‐7 cells led to a marked inhibition of luciferase activity by about 60%‐70% compared with controls, which was reversed by a let7a‐5p mimic inhibitor. Expression of this mimic led to a significant decrease in endogenous ABCC2 mRNA and protein levels in a Huh‐7 liver cell line, which could be blocked by expression of a let7a‐5p mimic inhibitor. Injection of a lentivirus let7a‐5p inhibitor into normal mouse liver or into mouse liver after common bile duct ligation led to a significant increase in endogenous Abcc2 mRNA and protein levels and a depletion of let7a‐5p mRNA levels compared with untreated, saline‐injected livers or livers treated with an inactive lentivirus control. Conclusion: These studies demonstrate that miR‐let7a‐5p is involved in regulating ABCC2/Abcc2 expression, and is aberrantly up‐regulated in obstructive cholestasis.

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MicroRNAs and their relevance to ABC transporters

Cited by 78 publications

References 66 publications

Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta

Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta

Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma

Up‐regulation of miR‐let7a‐5p Leads to Decreased Expression of ABCC2 in Obstructive Cholestasis

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