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

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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.

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Abbreviations

AHR:

Aryl hydrocarbon receptor

CYP:

Cytochrome P450

HCC:

Hepatocellular carcinoma

miRNA:

MicroRNA

mRNA:

Messenger RNA

NR1I2 (PXR):

Nuclear receptor 1I2, pregnane X receptor

qPCR:

Quantitative polymerase chain reaction

TCDD:

2,3,7,8-Tetrachlorodibenzo-p-dioxin

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Acknowledgements

The authors thank Karel Souček for instrument and core facility support, Petra Ovesná for statistical analysis and useful discussions, Zuzana Tylichová for help with EROD method, Jana Svobodová for technical assistance, Iva Lišková, Kateřina Svobodová, Martina Urbánková for technical support, Pavel Souček for help with antibody selection, and Jan Remšík for discussions.

Funding

Supported by Ministry of Health of the Czech Republic, grant No. 17-28231A. All rights reserved. The institutional support was provided by the long-term institutional funding of the Institute of Biophysics of the Czech Academy of Sciences (RVO: 68081707) and by Ministry of Health of the Czech Republic, DRO (UHHK, 00179906).

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Author notes

  1. Martin Krkoška and Jana Nekvindová share first authorship.

Authors and Affiliations

  1. Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 612 65, Brno, Czech Republic

    Martin Krkoška, Kateřina Nevědělová, Jan Vondráček, Jarmila Herůdková, Zuzana Tylichová & Alena Hyršlová Vaculová

  2. Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic

    Martin Krkoška & Kateřina Nevědělová

  3. Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic

    Jana Nekvindová, Veronika Zubáňová & Vladimír Palička

  4. Central European Institute of Technology, Masaryk University, Brno, Czech Republic

    Lenka Radová & Ondřej Slabý

  5. Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic

    Ondřej Slabý

  6. Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic

    Igor Kiss & Lucia Bohovicová

  7. Department of Oncological and Experimental Pathology, Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic

    Pavel Fabian

  8. Department of Surgery, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic

    Zdeněk Kala & Petr Kysela

  9. Department of Hematology, Oncology and Internal Medicine, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic

    Lenka Ostřížková

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Contributions

Conceptualization, AHV, JN, JV; methodology, JN, MK, KN, JH, ZT; software, LR; formal analysis, MK, KN, LR, JN, AHV; investigation, MK, JN, KN, VZ, JH, LB, PF, PK; resources, JV, OS, IK, VP, ZK, LO; data curation, MK, JN, LR, KN, JH, AHV; writing—original draft preparation, AHV, MK, JN; writing—review & editing, AHV, JV, MK, JN, KN; visualization, MK, LR, JN, AHV; supervision, AHV, JN, JV; project administration, AHV, JN, JV; funding acquisition, JN, AHV.

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Correspondence to Alena Hyršlová Vaculová.

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Krkoška, M., Nekvindová, J., Nevědělová, K. et al. Role of miR-653 and miR-29c in downregulation of CYP1A2 expression in hepatocellular carcinoma. Pharmacol. Rep 74, 148–158 (2022). https://doi.org/10.1007/s43440-021-00338-9

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