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.

• Keywords
• AHR, Biotransformation, CYP1A2, Hepatocellular carcinoma, microRNA,
• MeSH
• Biotransformation MeSH
• Cytochrome P-450 CYP1A2 metabolism   MeSH
• Down-Regulation MeSH
• Carcinoma, Hepatocellular * genetics   metabolism   MeSH
• Hepatocytes metabolism   MeSH
• Humans MeSH
• MicroRNAs metabolism   MeSH
• Cell Line, Tumor MeSH
• Liver Neoplasms * genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Xenobiotics metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• CYP1A2 protein, human MeSH Browser
• Cytochrome P-450 CYP1A2 MeSH
• MicroRNAs MeSH
• MIRN29C microRNA, human MeSH Browser
• MIRN653 microRNA, human MeSH Browser
• Xenobiotics MeSH

Pharmacogenomics is an evolving tool of precision medicine. Recently, due to the introduction of next-generation sequencing and projects generating "Big Data", a plethora of new genetic variants in pharmacogenes have been discovered. Cancer resistance is a major complication often preventing successful anticancer treatments. Pharmacogenomics of both somatic mutations in tumor cells and germline variants may help optimize targeted treatments and improve the response to conventional oncological therapy. In addition, integrative approaches combining copy number variations and long noncoding RNA profiling with germline and somatic variations seem to be a promising approach as well. In pharmacology, expression and enzyme activity are traditionally the more studied aspects of ATP-binding cassette transporters and cytochromes P450. In this review, we briefly introduce the field of pharmacogenomics and the advancements driven by next-generation sequencing and outline the possible roles of genetic variation in the two large pharmacogene superfamilies. Although the evidence needs further substantiation, somatic and copy number variants as well as rare variants and common polymorphisms in these genes could all affect response to cancer therapy. Regulation by long noncoding RNAs has also been shown to play a role. However, in all these areas, more comprehensive studies on larger sets of patients are needed.

• Keywords
• ATP-binding cassette transporters, cancer therapy, cytochromes P450, omics, personalized medicine, pharmacogenomics, response,
• Publication type
• Journal Article MeSH
• Review MeSH