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Role of miR-653 and miR-29c in downregulation of CYP1A2 expression in hepatocellular carcinoma

M. Krkoška, J. Nekvindová, K. Nevědělová, V. Zubáňová, L. Radová, J. Vondráček, J. Herůdková, O. Slabý, I. Kiss, L. Bohovicová, P. Fabian, Z. Tylichová, Z. Kala, P. Kysela, L. Ostřížková, V. Palička, A. Hyršlová Vaculová

. 2022 ; 74 (1) : 148-158. [pub] 20211115

Language English Country Switzerland

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc22011216

Grant support
17-28231A Ministerstvo Zdravotnictví Ceské Republiky
DRO (UHHK, 00179906) Ministerstvo Zdravotnictví Ceské Republiky
RVO:68081707 Akademie Věd České Republiky

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.

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$a Role of miR-653 and miR-29c in downregulation of CYP1A2 expression in hepatocellular carcinoma / $c M. Krkoška, J. Nekvindová, K. Nevědělová, V. Zubáňová, L. Radová, J. Vondráček, J. Herůdková, O. Slabý, I. Kiss, L. Bohovicová, P. Fabian, Z. Tylichová, Z. Kala, P. Kysela, L. Ostřížková, V. Palička, A. Hyršlová Vaculová
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$a 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.
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$a Nevědělová, Kateřina $u Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 612 65, Brno, Czech Republic $u Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
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$a Radová, Lenka $u Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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$a Herůdková, Jarmila $u Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 612 65, Brno, Czech Republic
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$a Kiss, Igor $u Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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$a Fabian, Pavel $u Department of Oncological and Experimental Pathology, Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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$a Tylichová, Zuzana $u Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 612 65, Brno, Czech Republic $1 https://orcid.org/0000000304335505
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$a Kala, Zdeněk $u Department of Surgery, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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$a Kysela, Petr $u Department of Surgery, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic $1 https://orcid.org/0000000334875246
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$a Ostřížková, Lenka $u Department of Hematology, Oncology and Internal Medicine, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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$a Palička, Vladimír $u Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic $1 https://orcid.org/0000000172361647 $7 jn99240000830
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