• Cytochrome P450 isoenzymes induce ROS during detoxification of chemical carcinogens that Besides causing DNA damage can lead to interference in multiple intracellular signaling pathways, notably MAPK/P13K-AKT/NF-KB/HIF-1
  • Mahdieh Bakhshayesh,1 Mansoureh Azadeh,2,*
    1. Zist Fanavari Novin Biotechnology Institute, Isfahan, Iran
    2. Zist Fanavari Novin Biotechnology Institute, Isfahan, Iran


  • Introduction: It is estimated that liver cancer is the fifth most frequently diagnosed cancer and the second most common cause of cancer-related deaths among men and that it is the seventh most frequently diagnosed cancer and the sixth leading cause of cancer-related deaths among women worldwide[1][2]. In contrast to men, women experience relatively low incidences and mortality rates from Hepatocellular carcinoma (HCC) [1]. CYP1A2 and CYP2C19 encode members of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids[3][4]. CYP1A2 and CYP2C19 may be associated with the occurrence of HCC. Cytochrome P2C (CYP2C) subfamily members (CYP2C19) are known to participate in clinical drug metabolism and are known to metabolize many xenobiotics, including the anticonvulsive drug mephenytoin, omeprazole, diazepam and some barbiturates that cause chemical carcinogenesis[5].
  • Methods: GSE112790 dataset Affymetrix was chosen and Microarray analysis was based on the bioinformatics tools (R programming language and online databases). to find differentially expressed genes (DEGs) in HCC samples compared to (Fifteen adjacent liver tissues obtained from patients with metastasis of colorectal cancer who had not received chemotherapy were used as control.) [6]. The GEO online database was used to find this dataset. In this study 54,676 genes were analyzed. The limma was used to conduct the DEG analysis on expression data, 144 low-expression genes and 172 high-expression genes were identified, which were selected for subsequent experimental research. The genes with logFC > 2 & logFC < -2 are considered as the differentially expressed genes (DEGs) in this dataset. The adjusted p-value (adj. P. Value) < 0.001 is considered the statistical significance level. Interaction between microRNA and LNCRNA using LNCRresearch was investigated. The Pathway enrichment analysis was carried out using KEGG and Reactome's online databases. All miRNAs were regained from DIANA-Tar Base v.8 and miRNA-mRNA interactions were investigated. The expression of lncRNAs in different tissues has been examined by the lnCAR databases. The expression of genes in HCC was compared by Gepia2 databases. The protein-protein interaction analysis has made by STRING online software.
  • Results: we found that the expression of mRNAs CYP1A2 and CYP2C19 in tumor tissue from HCC patients compared to the control group has decreased (adj. P. Value < 0.001). Interaction analysis of CYP1A2 and CYP2C19 mRNAs with MALAT1and NEAT1 lncRNAs illustrated that these RNAs have a single local base-pairing interaction (Energy = -21.76 kcal/mol) and (Energy = -12.48 kcal/mol). miRNA interaction analysis revealed that hsa-miR-27a-3p could regulate the expression of CYP1A2, CYP2C19 mRNAs and MALAT1, NEAT1 lncRNAs in cell line HUH7.5 from liver tissue in an interaction axis. CYP1A2 and CYP2C19 have a significant interaction that Played an important role in linoleic acid metabolism. CYP1A2 and CYP2C19 could regulate the following signaling pathways: Chemical carcinogenesis-reactive oxygen species, Drug metabolism-cytochrome p450, Chemical carcinogenesis-DNA adducts and Chemical carcinogenesis-receptor activation. CYP1A2 plays a role in the Chemical carcinogenesis-reactive oxygen species (ROS), one example of which is the induction of oxidative stress. ROS are also generated due to induction the of the various cytochrome P450 isoenzymes during detoxification of chemical carcinogens. Increased ROS generation often has been linked to DNA damage that can lead to damage to bio-macromolecules, gene mutations, altered gene expression and activation of oncogenic pathways. Besides causing DNA damage, ROS further induces multiple intracellular signaling pathways, notably MAPK/P13K-AKT/NF-KB/HIF-1. These signaling routes can lead to cancer proliferation, angiogenesis and metastasis to exposed cells. Furthermore, this study showed that CYP2C subfamily members can interact with CYP1A2. Besides, metabolizing IQ and MeIQx, CYP1A2 can also form DNA adducts (dG‐C8‐MeIQx, dG‐N‐MeIQx). A variety of cancers, such as liver, lung, colon, and breast, can be affected by DNA adducts.
  • Conclusion: CYP1A2 and CYP2C19 mRNAs could be two prognostic biomarkers. MALAT1 and NEAT1 lncRNAs expression levels have a significant positive correlation with the expression of CYP1A2 and CYP2C19 mRNAs in HCC. Hsa-miR-27a-3p could form a complex network with CYP1A2, CYP2C19 mRNAs and MALAT1, NEAT1 lncRNAs in cell line HUH7.5 from liver tissue. CYP1A2 induces oxidative stress. Increased ROS generation besides DNA damage can lead to damage to bio-macromolecules, gene mutations, altered gene expression and activation of oncogenic pathways. ROS also further interferes in multiple intracellular signaling pathways, notably MAPK/P13K-AKT/NF-KB/HIF-1.
  • Keywords: HCC, MAPK/P13K-AKT/NF-KB/HIF-1 signaling pathways, ROS, complex network, MALAT1, NEAT1