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.
2021
Hýžďalová, Martina; Procházková, Jiřina; Strapáčová, Simona; Svržková, Lucie; Vacek, Ondřej; Fedr, Radek; Andrysík, Zdeněk; Hrubá, Eva; Líbalová, Helena; Kléma, Jiří; Topinka, Jan; Mašek, Josef; Souček, Karel; Vondráček, Jan; Machala, Miroslav
In: Chemosphere, vol. 263, pp. 128126, 2021, ISSN: 1879-1298 0045-6535, (Place: England).
Abstract | Links | BibTeX | Tags: *Carcinoma, *Lung Neoplasms/genetics, Aryl Hydrocarbon/genetics, BaP, Benzo(a)pyrene/toxicity, Cell Proliferation, EMT, Epithelial Cells, Humans, Lung, Lung carcinoma, Phenotype, Receptors, TCDD, Tumor progression
@article{hyzdalova_prolonged_2021,
title = {A prolonged exposure of human lung carcinoma epithelial cells to benzo[a]pyrene induces p21-dependent epithelial-to-mesenchymal transition (EMT)-like phenotype.},
author = {Martina Hýžďalová and Jiřina Procházková and Simona Strapáčová and Lucie Svržková and Ondřej Vacek and Radek Fedr and Zdeněk Andrysík and Eva Hrubá and Helena Líbalová and Jiří Kléma and Jan Topinka and Josef Mašek and Karel Souček and Jan Vondráček and Miroslav Machala},
doi = {10.1016/j.chemosphere.2020.128126},
issn = {1879-1298 0045-6535},
year = {2021},
date = {2021-01-01},
journal = {Chemosphere},
volume = {263},
pages = {128126},
abstract = {Deciphering the role of the aryl hydrocarbon receptor (AhR) in lung cancer cells may help us to better understand the role of toxic AhR ligands in lung carcinogenesis, including cancer progression. We employed human lung carcinoma A549 cells to investigate their fate after continuous two-week exposure to model AhR agonists, genotoxic benzo[a]pyrene (BaP; 1 μM) and non-genotoxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 nM). While TCDD increased proliferative rate of A549 cells, exposure to BaP decreased cell proliferation and induced epithelial-to-mesenchymal transition (EMT)-like phenotype, which was associated with enhanced cell migration, invasion, and altered cell morphology. Although TCDD also suppressed expression of E-cadherin and activated some genes linked to EMT, it did not induce the EMT-like phenotype. The results of transcriptomic analysis, and the opposite effects of BaP and TCDD on cell proliferation, indicated that a delay in cell cycle progression, together with a slight increase of senescence (when coupled with AhR activation), favors the induction of EMT-like phenotype. The shift towards EMT-like phenotype observed after simultaneous treatment with TCDD and mitomycin C (an inhibitor of cell proliferation) confirmed the hypothesis. Since BaP decreased cell proliferative rate via induction of p21 expression, we generated the A549 cell model with reduced p21 expression and exposed it to BaP for two weeks. The p21 knockdown suppressed the BaP-mediated EMT-like phenotype in A549 cells, thus confirming that a delayed cell cycle progression, together with p21-dependent induction of senescence-related chemokine CCL2, may contribute to induction of EMT-like cell phenotype in lung cells exposed to genotoxic AhR ligands.},
note = {Place: England},
keywords = {*Carcinoma, *Lung Neoplasms/genetics, Aryl Hydrocarbon/genetics, BaP, Benzo(a)pyrene/toxicity, Cell Proliferation, EMT, Epithelial Cells, Humans, Lung, Lung carcinoma, Phenotype, Receptors, TCDD, Tumor progression},
pubstate = {published},
tppubtype = {article}
}
Deciphering the role of the aryl hydrocarbon receptor (AhR) in lung cancer cells may help us to better understand the role of toxic AhR ligands in lung carcinogenesis, including cancer progression. We employed human lung carcinoma A549 cells to investigate their fate after continuous two-week exposure to model AhR agonists, genotoxic benzo[a]pyrene (BaP; 1 μM) and non-genotoxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 nM). While TCDD increased proliferative rate of A549 cells, exposure to BaP decreased cell proliferation and induced epithelial-to-mesenchymal transition (EMT)-like phenotype, which was associated with enhanced cell migration, invasion, and altered cell morphology. Although TCDD also suppressed expression of E-cadherin and activated some genes linked to EMT, it did not induce the EMT-like phenotype. The results of transcriptomic analysis, and the opposite effects of BaP and TCDD on cell proliferation, indicated that a delay in cell cycle progression, together with a slight increase of senescence (when coupled with AhR activation), favors the induction of EMT-like phenotype. The shift towards EMT-like phenotype observed after simultaneous treatment with TCDD and mitomycin C (an inhibitor of cell proliferation) confirmed the hypothesis. Since BaP decreased cell proliferative rate via induction of p21 expression, we generated the A549 cell model with reduced p21 expression and exposed it to BaP for two weeks. The p21 knockdown suppressed the BaP-mediated EMT-like phenotype in A549 cells, thus confirming that a delayed cell cycle progression, together with p21-dependent induction of senescence-related chemokine CCL2, may contribute to induction of EMT-like cell phenotype in lung cells exposed to genotoxic AhR ligands.