2022
Krkoška, Martin; Nekvindová, Jana; Nevědělová, Kateřina; Zubáňová, Veronika; Radová, Lenka; Vondráček, Jan; Herůdková, Jarmila; Slabý, Ondřej; Kiss, Igor; Bohovicová, Lucia; Fabian, Pavel; Tylichová, Zuzana; Kala, Zdeněk; Kysela, Petr; Ostřížková, Lenka; Palička, Vladimír; Vaculová, Alena Hyršlová
Role of miR-653 and miR-29c in downregulation of CYP1A2 expression in hepatocellular carcinoma. Journal Article
In: Pharmacological reports : PR, vol. 74, no. 1, pp. 148–158, 2022, ISSN: 2299-5684 1734-1140, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: *Carcinoma, *Liver Neoplasms/genetics/metabolism, AhR, Biotransformation, Cell Line, CYP1A2, Cytochrome P-450 CYP1A2/*metabolism, Down-Regulation, Gene Expression Regulation, Hepatocellular carcinoma, Hepatocellular/genetics/metabolism, Hepatocytes/metabolism, Humans, MicroRNA, MicroRNAs/*metabolism, Neoplastic, Tumor, Xenobiotics/metabolism
@article{krkoska_role_2022,
title = {Role of miR-653 and miR-29c in downregulation of CYP1A2 expression in hepatocellular carcinoma.},
author = {Martin Krkoška and Jana Nekvindová and Kateřina Nevědělová and Veronika Zubáňová and Lenka Radová and Jan Vondráček and Jarmila Herůdková and Ondřej Slabý and Igor Kiss and Lucia Bohovicová and Pavel Fabian and Zuzana Tylichová and Zdeněk Kala and Petr Kysela and Lenka Ostřížková and Vladimír Palička and Alena Hyršlová Vaculová},
doi = {10.1007/s43440-021-00338-9},
issn = {2299-5684 1734-1140},
year = {2022},
date = {2022-02-01},
journal = {Pharmacological reports : PR},
volume = {74},
number = {1},
pages = {148–158},
abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to the worldwide cancer burden. Recent studies on HCC have demonstrated dramatic alterations in expression of several cytochrome P450 (CYP) family members that play a crucial role in biotransformation of many drugs and other xenobiotics; however, the mechanisms responsible for their deregulation remain unclear. METHODS: We investigated a potential involvement of miRNAs in downregulation of expression of CYPs observed in HCC tumors. We compared miRNA expression profiles (TaqMan Array Human MicroRNA v3.0 TLDA qPCR) between HCC human patient tumors with strong (CYP-) and weak/no (CYP+) downregulation of drug-metabolizing CYPs. The role of significantly deregulated miRNAs in modulation of expression of the CYPs and associated xenobiotic receptors was then investigated in human liver HepaRG cells transfected with relevant miRNA mimics or inhibitors. RESULTS: We identified five differentially expressed miRNAs in CYP- versus CYP+ tumors, namely miR-29c, miR-125b1, miR-505, miR-653 and miR-675. The two most-upregulated miRNAs found in CYP- tumor samples, miR-29c and miR-653, were found to act as efficient suppressors of CYP1A2 or AHR expression. CONCLUSIONS: Our results revealed a novel role of miR-653 and miR-29c in regulation of expresion of CYPs involved in crucial biotransformation processes in liver, which are often deregulated during liver cancer progression.},
note = {Place: Switzerland},
keywords = {*Carcinoma, *Liver Neoplasms/genetics/metabolism, AhR, Biotransformation, Cell Line, CYP1A2, Cytochrome P-450 CYP1A2/*metabolism, Down-Regulation, Gene Expression Regulation, Hepatocellular carcinoma, Hepatocellular/genetics/metabolism, Hepatocytes/metabolism, Humans, MicroRNA, MicroRNAs/*metabolism, Neoplastic, Tumor, Xenobiotics/metabolism},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to the worldwide cancer burden. Recent studies on HCC have demonstrated dramatic alterations in expression of several cytochrome P450 (CYP) family members that play a crucial role in biotransformation of many drugs and other xenobiotics; however, the mechanisms responsible for their deregulation remain unclear. METHODS: We investigated a potential involvement of miRNAs in downregulation of expression of CYPs observed in HCC tumors. We compared miRNA expression profiles (TaqMan Array Human MicroRNA v3.0 TLDA qPCR) between HCC human patient tumors with strong (CYP-) and weak/no (CYP+) downregulation of drug-metabolizing CYPs. The role of significantly deregulated miRNAs in modulation of expression of the CYPs and associated xenobiotic receptors was then investigated in human liver HepaRG cells transfected with relevant miRNA mimics or inhibitors. RESULTS: We identified five differentially expressed miRNAs in CYP- versus CYP+ tumors, namely miR-29c, miR-125b1, miR-505, miR-653 and miR-675. The two most-upregulated miRNAs found in CYP- tumor samples, miR-29c and miR-653, were found to act as efficient suppressors of CYP1A2 or AHR expression. CONCLUSIONS: Our results revealed a novel role of miR-653 and miR-29c in regulation of expresion of CYPs involved in crucial biotransformation processes in liver, which are often deregulated during liver cancer progression.
2018
Pěnčíková, Kateřina; Brenerová, Petra; Svržková, Lucie; Hrubá, Eva; Pálková, Lenka; Vondráček, Jan; Lehmler, Hans-Joachim; Machala, Miroslav
Atropisomers of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro. Journal Article
In: Environmental science and pollution research international, vol. 25, no. 17, pp. 16411–16419, 2018, ISSN: 1614-7499 0944-1344, (Place: Germany).
Abstract | Links | BibTeX | Tags: Androgen receptor, Animals, Atropisomer, Biotransformation, Chiral, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/*chemistry/metabolism, Estrogen receptors, Humans, Polychlorinated biphenyl, Polychlorinated Biphenyls/*chemistry, Pregnane X receptor, Receptors, Stereoisomerism, Steroid/chemistry/metabolism
@article{pencikova_atropisomers_2018,
title = {Atropisomers of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro.},
author = {Kateřina Pěnčíková and Petra Brenerová and Lucie Svržková and Eva Hrubá and Lenka Pálková and Jan Vondráček and Hans-Joachim Lehmler and Miroslav Machala},
doi = {10.1007/s11356-017-0683-x},
issn = {1614-7499 0944-1344},
year = {2018},
date = {2018-06-01},
journal = {Environmental science and pollution research international},
volume = {25},
number = {17},
pages = {16411–16419},
abstract = {PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (-)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (-)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral ortho-substituted PCB congeners.},
note = {Place: Germany},
keywords = {Androgen receptor, Animals, Atropisomer, Biotransformation, Chiral, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/*chemistry/metabolism, Estrogen receptors, Humans, Polychlorinated biphenyl, Polychlorinated Biphenyls/*chemistry, Pregnane X receptor, Receptors, Stereoisomerism, Steroid/chemistry/metabolism},
pubstate = {published},
tppubtype = {article}
}
PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (-)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (-)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral ortho-substituted PCB congeners.