Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition via the regulation of target ADME gene expression
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摘要
Drug-metabolizing enzymes, transporters, and nuclear receptors are essential for the absorption, distribution, metabolism, and excretion(ADME) of drugs and xenobiotics. MicroRNAs participate in the regulation of ADME gene expression via imperfect complementary Watson–Crick base pairings with target transcripts. We have previously reported that Cytochrome P450 3A4(CYP3A4) and ATP-binding cassette sub-family G member 2(ABCG2) are regulated by miR-27b-3p and miR-328-3p,respectively. Here we employed our newly established RNA bioengineering technology to produce bioengineered RNA agents(BERA), namely BERA/miR-27b-3p and BERA/miR-328-3p, via fermentation. When introduced into human cells, BERA/miR-27b-3p and BERA/miR-328-3p were selectively processed to target miRNAs and thus knock down CYP3A4 and ABCG2 mRNA and their protein levels,respectively, as compared to cells treated with vehicle or control RNA. Consequently, BERA/miR-27b-3p led to a lower midazolam 10-hydroxylase activity, indicating the reduction of CYP3A4 activity. Likewise,BERA/miR-328-3p treatment elevated the intracellular accumulation of anticancer drug mitoxantrone, a classic substrate of ABCG2, hence sensitized the cells to chemotherapy. The results indicate that biologic miRNA agents made by RNA biotechnology may be applied to research on miRNA functions in the regulation of drug metabolism and disposition that could provide insights into the development of more effective therapies.
Drug-metabolizing enzymes, transporters, and nuclear receptors are essential for the absorption, distribution, metabolism, and excretion(ADME) of drugs and xenobiotics. MicroRNAs participate in the regulation of ADME gene expression via imperfect complementary Watson–Crick base pairings with target transcripts. We have previously reported that Cytochrome P450 3A4(CYP3A4) and ATP-binding cassette sub-family G member 2(ABCG2) are regulated by miR-27b-3p and miR-328-3p,respectively. Here we employed our newly established RNA bioengineering technology to produce bioengineered RNA agents(BERA), namely BERA/miR-27b-3p and BERA/miR-328-3p, via fermentation. When introduced into human cells, BERA/miR-27b-3p and BERA/miR-328-3p were selectively processed to target miRNAs and thus knock down CYP3A4 and ABCG2 mRNA and their protein levels,respectively, as compared to cells treated with vehicle or control RNA. Consequently, BERA/miR-27b-3p led to a lower midazolam 10-hydroxylase activity, indicating the reduction of CYP3A4 activity. Likewise,BERA/miR-328-3p treatment elevated the intracellular accumulation of anticancer drug mitoxantrone, a classic substrate of ABCG2, hence sensitized the cells to chemotherapy. The results indicate that biologic miRNA agents made by RNA biotechnology may be applied to research on miRNA functions in the regulation of drug metabolism and disposition that could provide insights into the development of more effective therapies.
Drug-metabolizing enzymes, transporters, and nuclear receptors are essential for the absorption, distribution, metabolism, and excretion(ADME) of drugs and xenobiotics. MicroRNAs participate in the regulation of ADME gene expression via imperfect complementary Watson–Crick base pairings with target transcripts. We have previously reported that Cytochrome P450 3A4(CYP3A4) and ATP-binding cassette sub-family G member 2(ABCG2) are regulated by miR-27b-3p and miR-328-3p,respectively. Here we employed our newly established RNA bioengineering technology to produce bioengineered RNA agents(BERA), namely BERA/miR-27b-3p and BERA/miR-328-3p, via fermentation. When introduced into human cells, BERA/miR-27b-3p and BERA/miR-328-3p were selectively processed to target miRNAs and thus knock down CYP3A4 and ABCG2 mRNA and their protein levels,respectively, as compared to cells treated with vehicle or control RNA. Consequently, BERA/miR-27b-3p led to a lower midazolam 10-hydroxylase activity, indicating the reduction of CYP3A4 activity. Likewise,BERA/miR-328-3p treatment elevated the intracellular accumulation of anticancer drug mitoxantrone, a classic substrate of ABCG2, hence sensitized the cells to chemotherapy. The results indicate that biologic miRNA agents made by RNA biotechnology may be applied to research on miRNA functions in the regulation of drug metabolism and disposition that could provide insights into the development of more effective therapies.
引文
1.Lu AY.Drug-metabolism research challenges in the new millennium:individual variability in drug therapy and drug safety.Drug Metab Dispos 1998;26:1217-22.
2.Yu AM,Pan YZ.Noncoding microRNAs:small RNAs play a big role in regulation of ADME?.Acta Pharm Sin B 2012;2:93-101.
3.Zanger UM,Schwab M.Cytochrome P450 enzymes in drug metabolism:regulation of gene expression,enzyme activities,and impact of genetic variation.Pharmacol Ther 2013;138:103-41.
4.Tracy TS,Chaudhry AS,Prasad B,Thummel KE,Schuetz EG,Zhong XB,et al.Interindividual variability in cytochrome P450-mediated drug metabolism.Drug Metab Dispos 2016;44:343-51.
5.Manikandan P,Nagini S.Cytochrome P450 structure,function and clinical significance:a review.Curr Drug Targets 2018;19:38-54.
6.Gu X,Xiao Q,Ruan Q,Shu Y,Dongre A,Iyer R,et al.Comparative untargeted proteomic analysis of ADME proteins and tumor antigens for tumor cell lines.Acta Pharm Sin B 2018;8:252-60.
7.Yu AM,Ingelman-Sundberg M,Cherrington NJ,Aleksunes LM,Zanger UM,Xie W,et al.Regulation of drug metabolism and toxicity by multiple factors of genetics,epigenetics,lncRNAs,gut microbiota,and diseases:a meeting report of the 21stInternational Symposium on Microsomes and Drug Oxidations(MDO).Acta Pharm Sin B2017;7:241-8.
8.Krek A,Grün D,Poy MN,Wolf R,Rosenberg L,Epstein EJ,et al.Combinatorial microRNA target predictions.Nat Gen 2005;37:495-500.
9.Yokoi T,Nakajima M.microRNAs as mediators of drug toxicity.Annu Rev Pharmacol Toxicol 2013;53:377-400.
10.Ingelman-Sundberg M,Zhong XB,Hankinson O,Beedanagari S,Yu AM,Peng L,et al.Potential role of epigenetic mechanisms in the regulation of drug metabolism and transport.Drug Metab Dispos2013;41:1725-31.
11.Yu AM,Tian Y,Tu MJ,Ho PY,Jilek JL.MicroRNA pharmacoepigenetics:posttranscriptional regulation mechanisms behind variable drug disposition and strategy to develop more effective therapy.Drug Metab Dispos 2016;44:308-19.
12.Nakano M,Nakajima M.Current knowledge of microRNA-mediated regulation of drug metabolism in humans.Expert Opin Drug Metab Toxicol 2018;14:493-504.
13.Tsuchiya Y,Nakajima M,Takagi S,Taniya T,Yokoi T.MicroRNAregulates the expression of human cytochrome P450 1B1.Cancer Res2006;66:9090-8.
14.Chuturgoon AA,Phulukdaree A,Moodley D.Fumonisin B1modulates expression of human cytochrome P450 1b1 in human hepatoma(Hepg2)cells by repressing Mir-27b.Toxicol Lett 2014;227:50-5.
15.Pan YZ,Gao W,Yu AM.MicroRNAs regulate CYP3A4 expression via direct and indirect targeting.Drug Metab Dispos 2009;37:2112-7.
16.Ekstr?m L,Skilving I,Ovesj?ML,Aklillu E,Nylén H,Rane A,et al.miRNA-27b levels are associated with CYP3A activity in vitro and in vivo.Pharmacol Res Perspect 2015;3:e00192.
17.Apellániz-Ruiz M,Inglada-Pérez L,Naranjo ME,Sánchez L,Mancikova V,Currás-Freixes M,et al.High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.Pharmacogenomics J2015;15:288-92.
18.Wrighton SA,Stevens JC.The human hepatic cytochromes P450involved in drug metabolism.Crit Rev Toxicol 1992;22:1-21.
19.Li MM,Wang WP,Wu WJ,Huang M,Yu AM.Rapid production of novel pre-microRNA agent hsa-mir-27b in Escherichia coli using recombinant RNA technology for functional studies in mammalian cells.Drug Metab Dispos 2014;42:1791-5.
20.Ji J,Zhang J,Huang G,Qian J,Wang X,Mei S.Over-expressed microRNA-27a and 27b influence fat accumulation and cell proliferation during rat hepatic stellate cell activation.FEBS Lett2009;583:759-66.
21.Pan YZ,Morris ME,Yu AM.MicroRNA-328 negatively regulates the expression of breast cancer resistance protein(BCRP/ABCG2)in human cancer cells.Mol Pharmacol 2009;75:1374-9.
22.Li X,Pan YZ,Seigel GM,Hu ZH,Huang M,Yu AM.Breast cancer resistance protein BCRP/ABCG2 regulatory microRNAs(hsa-miR-328,-519c and-520h)and their differential expression in stem-like ABCG2tcancer cells.Biochem Pharmacol 2011;81:783-92.
23.To KK,Leung WW,Ng SS.Exploiting a novel miR-519c-HuR-ABCG2 regulatory pathway to overcome chemoresistance in colorectal cancer.Exp Cell Res 2015;338:222-31.
24.Jiao X,Zhao L,Ma M,Bai X,He M,Yan Y,et al.MiR-181a enhances drug sensitivity in mitoxantone-resistant breast cancer cells by targeting breast cancer resistance protein(BCRP/ABCG2).Breast Cancer Res Treat 2013;139:717-30.
25.Ma MT,He M,Wang Y,Jiao XY,Zhao L,Bai XF,et al.Mi R-487a resensitizes mitoxantrone(MX)-resistant breast cancer cells(MCF-7/MX)to MX by targeting breast cancer resistance protein(BCRP/ABCG2).Cancer Lett 2013;339:107-15.
26.Ho PY,Yu AM.Bioengineering of noncoding RNAs for research agents and therapeutics.Wiley Interdiscip Rev RNA 2016;7:186-97.
27.Chen QX,Wang WP,Zeng S,Urayama S,Yu AM.A general approach to high-yield biosynthesis of chimeric RNAs bearing various types of functional small RNAs for broad applications.Nucl Acids Res2015;43:3857-69.
28.Ho PY,Duan Z,Batra N,Jilek JL,Tu MJ,Qiu JX,et al.Bioengineered noncoding RNAs selectively change cellular mirnome profiles for cancer therapy.J Pharmacol Exp Ther 2018;365:494-506.
29.Li MM,Addepalli B,Tu MJ,Chen QX,Wang WP,Limbach PA,et al.Chimeric microRNA-1291 biosynthesized efficiently in Escherichia coli is effective to reduce target gene expression in human carcinoma cells and improve chemosensitivity.Drug Metab Dispos2015;43:1129-36.
30.Wang WP,Ho PY,Chen QX,Addepalli B,Limbach PA,Li MM,et al.Bioengineering novel chimeric microRNA-34a for prodrug cancer therapy:high-yield expression and purification,and structural and functional characterization.J Pharmacol Exp Ther 2015;354:131-41.
31.Li PC,Tu MJ,Ho PY,Jilek JL,Duan Z,Zhang QY,et al.Bioengineered NRF2-siRNA is effective to interfere with NRF2pathways and improve chemosensitivity of human cancer cells.Drug Metab Dispos 2018;46:2-10.
32.Ho PY,Duan Z,Batra N,Jilek JL,Tu MJ,Qiu JX,et al.Bioengineered ncRNAs selectively change cellular miRNome profiles for cancer therapy.J Pharmacol Exp Ther 2018;365:494-506.
33.Ponchon L,Beauvais G,Nonin-Lecomte S,Dardel F.A generic protocol for the expression and purification of recombinant RNA in Escherichia coli using a t RNA scaffold.Nat Protoc 2009;4:947-59.
34.Thummel KE,Brimer C,Yasuda K,Thottassery J,Senn T,Lin Y,et al.Transcriptional control of intestinal cytochrome P-4503A by 1α,25-dihydroxy vitamin D3.Mol Pharmacol 2001;60:1399-406.
35.Jilek JL,Tian Y,Yu AM.Effects of MicroRNA-34a on the pharmacokinetics of cytochrome P450 probe drugs in mice.Drug Metab Dispos 2017;45:512-22.
36.Olsen LR,Gabel-Jensen C,Wubshet SG,Kongstad KT,Janfelt C,Badolo L,et al.Characterization of midazolam metabolism in locusts:the role of a CYP3A4-like enzyme in the formation of 10-OH and 4-OH midazolam.Xenobiotica 2016;46:99-107.
37.Pillai VC,Strom SC,Caritis SN,Venkataramanan R.A sensitive and specific CYP cocktail assay for the simultaneous assessment of human cytochrome P450 activities in primary cultures of human hepatocytes using LC-MS/MS.J Pharm Biomed Anal 2013;74:126-32.
38.Andersson S,Antonsson M,Elebring M,Jansson-L?fmark R,Weidolf L.Drug metabolism and pharmacokinetic strategies for oligonucleotide-and mRNA-based drug development.Drug Discov Today2018;23:1733-45.
39.Lauschke VM,Barragan I,Ingelman-Sundberg M.Pharmacoepigenetics and toxicoepigenetics:novel mechanistic insights and therapeutic opportunities.Annu Rev Pharmacol Toxicol 2018;58:161-85.
40.Jackson SM,Manolaridis I,Kowal J,Zechner M,Taylor NMI,Bause M,et al.Structural basis of small-molecule inhibition of human multidrug transporter ABCG2.Nat Struct Mol Biol 2018;25:333-40.
41.Evseenko DA,Paxton JW,Keelan JA.ABC drug transporter expression and functional activity in trophoblast-like cell lines and differentiating primary trophoblast.Am J Physiol Regul Integr Comp Physiol 2006;290:R1357-65.
42.Arvey A,Larsson E,Sander C,Leslie CS,Marks DS.Target mRNAabundance dilutes microRNA and siRNA activity.Mol Syst Biol2010;6:363.
43.Ahadi A,Sablok G,Hutvagner G.miRTar2GO:a novel rule-based model learning method for cell line specific microRNA target prediction that integrates Ago2 CLIP-Seq and validated microRNA-target interaction data.Nucl Acids Res 2017;45:e42.
44.Francois LN,Gorczyca L,Du J,Bircsak KM,Yen E,Wen X,et al.Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling.Placenta 2017;51:57-63.
45.Erhard F,Haas J,Lieber D,Malterer G,Jaskiewicz L,Zavolan M,et al.Widespread context dependency of microRNA-mediated regulation.Genome Res 2014;24:906-19.
46.Choi YH,Yu AM.ABC transporters in multidrug resistance and pharmacokinetics,and strategies for drug development.Curr Pharm Des 2014;20:793-807.
2.Yu AM,Pan YZ.Noncoding microRNAs:small RNAs play a big role in regulation of ADME?.Acta Pharm Sin B 2012;2:93-101.
3.Zanger UM,Schwab M.Cytochrome P450 enzymes in drug metabolism:regulation of gene expression,enzyme activities,and impact of genetic variation.Pharmacol Ther 2013;138:103-41.
4.Tracy TS,Chaudhry AS,Prasad B,Thummel KE,Schuetz EG,Zhong XB,et al.Interindividual variability in cytochrome P450-mediated drug metabolism.Drug Metab Dispos 2016;44:343-51.
5.Manikandan P,Nagini S.Cytochrome P450 structure,function and clinical significance:a review.Curr Drug Targets 2018;19:38-54.
6.Gu X,Xiao Q,Ruan Q,Shu Y,Dongre A,Iyer R,et al.Comparative untargeted proteomic analysis of ADME proteins and tumor antigens for tumor cell lines.Acta Pharm Sin B 2018;8:252-60.
7.Yu AM,Ingelman-Sundberg M,Cherrington NJ,Aleksunes LM,Zanger UM,Xie W,et al.Regulation of drug metabolism and toxicity by multiple factors of genetics,epigenetics,lncRNAs,gut microbiota,and diseases:a meeting report of the 21stInternational Symposium on Microsomes and Drug Oxidations(MDO).Acta Pharm Sin B2017;7:241-8.
8.Krek A,Grün D,Poy MN,Wolf R,Rosenberg L,Epstein EJ,et al.Combinatorial microRNA target predictions.Nat Gen 2005;37:495-500.
9.Yokoi T,Nakajima M.microRNAs as mediators of drug toxicity.Annu Rev Pharmacol Toxicol 2013;53:377-400.
10.Ingelman-Sundberg M,Zhong XB,Hankinson O,Beedanagari S,Yu AM,Peng L,et al.Potential role of epigenetic mechanisms in the regulation of drug metabolism and transport.Drug Metab Dispos2013;41:1725-31.
11.Yu AM,Tian Y,Tu MJ,Ho PY,Jilek JL.MicroRNA pharmacoepigenetics:posttranscriptional regulation mechanisms behind variable drug disposition and strategy to develop more effective therapy.Drug Metab Dispos 2016;44:308-19.
12.Nakano M,Nakajima M.Current knowledge of microRNA-mediated regulation of drug metabolism in humans.Expert Opin Drug Metab Toxicol 2018;14:493-504.
13.Tsuchiya Y,Nakajima M,Takagi S,Taniya T,Yokoi T.MicroRNAregulates the expression of human cytochrome P450 1B1.Cancer Res2006;66:9090-8.
14.Chuturgoon AA,Phulukdaree A,Moodley D.Fumonisin B1modulates expression of human cytochrome P450 1b1 in human hepatoma(Hepg2)cells by repressing Mir-27b.Toxicol Lett 2014;227:50-5.
15.Pan YZ,Gao W,Yu AM.MicroRNAs regulate CYP3A4 expression via direct and indirect targeting.Drug Metab Dispos 2009;37:2112-7.
16.Ekstr?m L,Skilving I,Ovesj?ML,Aklillu E,Nylén H,Rane A,et al.miRNA-27b levels are associated with CYP3A activity in vitro and in vivo.Pharmacol Res Perspect 2015;3:e00192.
17.Apellániz-Ruiz M,Inglada-Pérez L,Naranjo ME,Sánchez L,Mancikova V,Currás-Freixes M,et al.High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.Pharmacogenomics J2015;15:288-92.
18.Wrighton SA,Stevens JC.The human hepatic cytochromes P450involved in drug metabolism.Crit Rev Toxicol 1992;22:1-21.
19.Li MM,Wang WP,Wu WJ,Huang M,Yu AM.Rapid production of novel pre-microRNA agent hsa-mir-27b in Escherichia coli using recombinant RNA technology for functional studies in mammalian cells.Drug Metab Dispos 2014;42:1791-5.
20.Ji J,Zhang J,Huang G,Qian J,Wang X,Mei S.Over-expressed microRNA-27a and 27b influence fat accumulation and cell proliferation during rat hepatic stellate cell activation.FEBS Lett2009;583:759-66.
21.Pan YZ,Morris ME,Yu AM.MicroRNA-328 negatively regulates the expression of breast cancer resistance protein(BCRP/ABCG2)in human cancer cells.Mol Pharmacol 2009;75:1374-9.
22.Li X,Pan YZ,Seigel GM,Hu ZH,Huang M,Yu AM.Breast cancer resistance protein BCRP/ABCG2 regulatory microRNAs(hsa-miR-328,-519c and-520h)and their differential expression in stem-like ABCG2tcancer cells.Biochem Pharmacol 2011;81:783-92.
23.To KK,Leung WW,Ng SS.Exploiting a novel miR-519c-HuR-ABCG2 regulatory pathway to overcome chemoresistance in colorectal cancer.Exp Cell Res 2015;338:222-31.
24.Jiao X,Zhao L,Ma M,Bai X,He M,Yan Y,et al.MiR-181a enhances drug sensitivity in mitoxantone-resistant breast cancer cells by targeting breast cancer resistance protein(BCRP/ABCG2).Breast Cancer Res Treat 2013;139:717-30.
25.Ma MT,He M,Wang Y,Jiao XY,Zhao L,Bai XF,et al.Mi R-487a resensitizes mitoxantrone(MX)-resistant breast cancer cells(MCF-7/MX)to MX by targeting breast cancer resistance protein(BCRP/ABCG2).Cancer Lett 2013;339:107-15.
26.Ho PY,Yu AM.Bioengineering of noncoding RNAs for research agents and therapeutics.Wiley Interdiscip Rev RNA 2016;7:186-97.
27.Chen QX,Wang WP,Zeng S,Urayama S,Yu AM.A general approach to high-yield biosynthesis of chimeric RNAs bearing various types of functional small RNAs for broad applications.Nucl Acids Res2015;43:3857-69.
28.Ho PY,Duan Z,Batra N,Jilek JL,Tu MJ,Qiu JX,et al.Bioengineered noncoding RNAs selectively change cellular mirnome profiles for cancer therapy.J Pharmacol Exp Ther 2018;365:494-506.
29.Li MM,Addepalli B,Tu MJ,Chen QX,Wang WP,Limbach PA,et al.Chimeric microRNA-1291 biosynthesized efficiently in Escherichia coli is effective to reduce target gene expression in human carcinoma cells and improve chemosensitivity.Drug Metab Dispos2015;43:1129-36.
30.Wang WP,Ho PY,Chen QX,Addepalli B,Limbach PA,Li MM,et al.Bioengineering novel chimeric microRNA-34a for prodrug cancer therapy:high-yield expression and purification,and structural and functional characterization.J Pharmacol Exp Ther 2015;354:131-41.
31.Li PC,Tu MJ,Ho PY,Jilek JL,Duan Z,Zhang QY,et al.Bioengineered NRF2-siRNA is effective to interfere with NRF2pathways and improve chemosensitivity of human cancer cells.Drug Metab Dispos 2018;46:2-10.
32.Ho PY,Duan Z,Batra N,Jilek JL,Tu MJ,Qiu JX,et al.Bioengineered ncRNAs selectively change cellular miRNome profiles for cancer therapy.J Pharmacol Exp Ther 2018;365:494-506.
33.Ponchon L,Beauvais G,Nonin-Lecomte S,Dardel F.A generic protocol for the expression and purification of recombinant RNA in Escherichia coli using a t RNA scaffold.Nat Protoc 2009;4:947-59.
34.Thummel KE,Brimer C,Yasuda K,Thottassery J,Senn T,Lin Y,et al.Transcriptional control of intestinal cytochrome P-4503A by 1α,25-dihydroxy vitamin D3.Mol Pharmacol 2001;60:1399-406.
35.Jilek JL,Tian Y,Yu AM.Effects of MicroRNA-34a on the pharmacokinetics of cytochrome P450 probe drugs in mice.Drug Metab Dispos 2017;45:512-22.
36.Olsen LR,Gabel-Jensen C,Wubshet SG,Kongstad KT,Janfelt C,Badolo L,et al.Characterization of midazolam metabolism in locusts:the role of a CYP3A4-like enzyme in the formation of 10-OH and 4-OH midazolam.Xenobiotica 2016;46:99-107.
37.Pillai VC,Strom SC,Caritis SN,Venkataramanan R.A sensitive and specific CYP cocktail assay for the simultaneous assessment of human cytochrome P450 activities in primary cultures of human hepatocytes using LC-MS/MS.J Pharm Biomed Anal 2013;74:126-32.
38.Andersson S,Antonsson M,Elebring M,Jansson-L?fmark R,Weidolf L.Drug metabolism and pharmacokinetic strategies for oligonucleotide-and mRNA-based drug development.Drug Discov Today2018;23:1733-45.
39.Lauschke VM,Barragan I,Ingelman-Sundberg M.Pharmacoepigenetics and toxicoepigenetics:novel mechanistic insights and therapeutic opportunities.Annu Rev Pharmacol Toxicol 2018;58:161-85.
40.Jackson SM,Manolaridis I,Kowal J,Zechner M,Taylor NMI,Bause M,et al.Structural basis of small-molecule inhibition of human multidrug transporter ABCG2.Nat Struct Mol Biol 2018;25:333-40.
41.Evseenko DA,Paxton JW,Keelan JA.ABC drug transporter expression and functional activity in trophoblast-like cell lines and differentiating primary trophoblast.Am J Physiol Regul Integr Comp Physiol 2006;290:R1357-65.
42.Arvey A,Larsson E,Sander C,Leslie CS,Marks DS.Target mRNAabundance dilutes microRNA and siRNA activity.Mol Syst Biol2010;6:363.
43.Ahadi A,Sablok G,Hutvagner G.miRTar2GO:a novel rule-based model learning method for cell line specific microRNA target prediction that integrates Ago2 CLIP-Seq and validated microRNA-target interaction data.Nucl Acids Res 2017;45:e42.
44.Francois LN,Gorczyca L,Du J,Bircsak KM,Yen E,Wen X,et al.Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling.Placenta 2017;51:57-63.
45.Erhard F,Haas J,Lieber D,Malterer G,Jaskiewicz L,Zavolan M,et al.Widespread context dependency of microRNA-mediated regulation.Genome Res 2014;24:906-19.
46.Choi YH,Yu AM.ABC transporters in multidrug resistance and pharmacokinetics,and strategies for drug development.Curr Pharm Des 2014;20:793-807.