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Hepatocellular carcinoma: Gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450

J. Nekvindova, A. Mrkvicova, V. Zubanova, A. Hyrslova Vaculova, P. Anzenbacher, P. Soucek, L. Radova, O. Slaby, I. Kiss, J. Vondracek, A. Spicakova, L. Bohovicova, P. Fabian, Z. Kala, V. Palicka,

. 2020 ; 177 (-) : 113912. [pub] 20200313

Language English Country Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc20028039

Hepatocellular carcinoma (HCC) remains a highly prevalent and deadly disease, being among the top causes of cancer-related deaths worldwide. Despite the fact that the liver is the major site of biotransformation, studies on drug metabolizing enzymes in HCC are scarce. It is known that malignant transformation of hepatocytes leads to a significant alteration of their metabolic functions and overall deregulation of gene expression. Advanced stages of the disease are thus frequently associated with liver failure, and severe alteration of drug metabolism. However, the impact of dysregulation of metabolic enzymes on therapeutic efficacy and toxicity in HCC patients is largely unknown. Here we demonstrate a significant down-regulation in European Caucasian patients of cytochromes P450 (CYPs), the major xenobiotic-metabolizing enzymes, in HCC tumour samples as compared to their surrounding non-cancerous (reference) tissue. Moreover, we report for the first time the association of the unique CYP profiles with specific transcriptome changes, and interesting correlations with expression levels of nuclear receptors and with the histological grade of the tumours. Integrated analysis has suggested certain co-expression profiles of CYPs with lncRNAs that need to be further characterized. Patients with large tumours with down-regulated CYPs could be more vulnerable to drug toxicity; on the other hand, such tumours would eliminate drugs more slowly and should be more sensitive to pharmacotherapy (except in the case of pro-drugs where activation is necessary).

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$a Nekvindova, Jana $u Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Czech Republic. Electronic address: nekvindova@fnhk.cz.
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$a Hepatocellular carcinoma: Gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450 / $c J. Nekvindova, A. Mrkvicova, V. Zubanova, A. Hyrslova Vaculova, P. Anzenbacher, P. Soucek, L. Radova, O. Slaby, I. Kiss, J. Vondracek, A. Spicakova, L. Bohovicova, P. Fabian, Z. Kala, V. Palicka,
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$a Hepatocellular carcinoma (HCC) remains a highly prevalent and deadly disease, being among the top causes of cancer-related deaths worldwide. Despite the fact that the liver is the major site of biotransformation, studies on drug metabolizing enzymes in HCC are scarce. It is known that malignant transformation of hepatocytes leads to a significant alteration of their metabolic functions and overall deregulation of gene expression. Advanced stages of the disease are thus frequently associated with liver failure, and severe alteration of drug metabolism. However, the impact of dysregulation of metabolic enzymes on therapeutic efficacy and toxicity in HCC patients is largely unknown. Here we demonstrate a significant down-regulation in European Caucasian patients of cytochromes P450 (CYPs), the major xenobiotic-metabolizing enzymes, in HCC tumour samples as compared to their surrounding non-cancerous (reference) tissue. Moreover, we report for the first time the association of the unique CYP profiles with specific transcriptome changes, and interesting correlations with expression levels of nuclear receptors and with the histological grade of the tumours. Integrated analysis has suggested certain co-expression profiles of CYPs with lncRNAs that need to be further characterized. Patients with large tumours with down-regulated CYPs could be more vulnerable to drug toxicity; on the other hand, such tumours would eliminate drugs more slowly and should be more sensitive to pharmacotherapy (except in the case of pro-drugs where activation is necessary).
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$a Mrkvicová, Alena $u Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Czech Republic; Department of Medical Biochemistry, Charles University, Faculty of Medicine in Hradec Kralove, Czech Republic. Electronic address: MrkvicovaA@lfhk.cuni.cz. $7 xx0267751
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$a Zubanova, Veronika $u Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Czech Republic. Electronic address: veronikazubanova@gmail.com.
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$a Hyrslova Vaculova, Alena $u Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic. Electronic address: vaculova@ibp.cz.
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$a Anzenbacher, Pavel $u Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. Electronic address: pavel.anzenbacher@upol.cz.
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$a Soucek, Pavel $u Center for Toxicology and Health Safety, National Institute of Public Health, Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic. Electronic address: pavel.soucek@szu.cz.
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$a Radova, Lenka $u Central European Institute of Technology, Masaryk University, Brno, Czech Republic. Electronic address: lenka.radova@ceitec.muni.cz.
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$a Slaby, Ondrej $u Central European Institute of Technology, Masaryk University, Brno, Czech Republic; Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic. Electronic address: on.slaby@gmail.com.
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$a Kiss, Igor $u Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic. Electronic address: kiss@mou.cz.
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$a Vondracek, Jan $u Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic. Electronic address: vondracek@ibp.cz.
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$a Spicakova, Alena $u Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. Electronic address: alonek@centrum.cz.
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$a Bohovicova, Lucia $u Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic. Electronic address: bohovicova@mou.cz.
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$a Fabian, Pavel $u Department of Oncological and Experimental Pathology, Cancer Institute, Brno, Czech Republic. Electronic address: fabian@mou.cz.
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$a Kala, Zdenek $u Department of Surgery, University Hospital Brno, Czech Republic. Electronic address: Kala.Zdenek@fnbrno.cz.
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$a Palicka, Vladimir $u Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Czech Republic. Electronic address: palicka@lfhk.cuni.cz.
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