Gene Summary

Gene:CYP1A2; cytochrome P450 family 1 subfamily A member 2
Aliases: CP12, CYPIA2, P3-450, P450(PA)
Summary:This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The protein encoded by this gene localizes to the endoplasmic reticulum and its expression is induced by some polycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. Other xenobiotic substrates for this enzyme include caffeine, aflatoxin B1, and acetaminophen. The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cytochrome P450 1A2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Thyroid Diseases
  • Promoter Regions
  • CYP17
  • Colorectal Cancer
  • Arylamine N-Acetyltransferase
  • Statistics, Nonparametric
  • CYP1B1
  • Stomach Cancer
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1A2
  • Urban Population
  • Xenobiotics
  • Chromosome 15
  • Genotype
  • Xanthines
  • Case-Control Studies
  • Testicular Cancer
  • Carcinogens
  • Tissue Embedding
  • Breast Cancer
  • Prostate Cancer
  • Single Nucleotide Polymorphism
  • Neoplasms, Experimental
  • Publication Bias
  • Cytochrome P-450 Enzyme System
  • Genetic Predisposition
  • beta Carotene
  • Transfection
  • Lung Cancer
  • Practice Guidelines as Topic
  • Smoking
  • Tunisia
  • Risk Factors
  • Aryl Hydrocarbon Hydroxylases
  • Glutathione Transferase
  • Thailand
  • Risk Assessment
  • Surveys and Questionnaires
  • Sweden
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CYP1A2 (cancer-related)

Dusek J, Skoda J, Holas O, et al.
Stilbene compound trans-3,4,5,4´-tetramethoxystilbene, a potential anticancer drug, regulates constitutive androstane receptor (Car) target genes, but does not possess proliferative activity in mouse liver.
Toxicol Lett. 2019; 313:1-10 [PubMed] Related Publications
The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. Recently, trans-3,4,5,4´-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism.

Zhang GH, Chen MM, Kai JY, et al.
Molecular profiling of mucinous epithelial ovarian cancer by weighted gene co-expression network analysis.
Gene. 2019; 709:56-64 [PubMed] Related Publications
PURPOSE: In order to identify the molecular characteristics and improve the efficacy of early diagnosis of mucinous epithelial ovarian cancer (mEOC), here, the transcriptome profiling by weighted gene co-expression network analysis (WGCNA) has been proposed as an effective method.
METHODS: The gene expression dataset GSE26193 was reanalyzed with a systematical approach, WGCNA. mEOC-related gene co-expression modules were detected and the functional enrichments of these modules were performed at GO and KEGG terms. Ten hub genes in the mEOC-related modules were validated using two independent datasets GSE44104 and GSE30274.
RESULTS: 11 co-expressed gene modules were identified by WGCNA based on 4917 genes and 99 epithelial ovarian cancer samples. The turquoise module was found to be significantly associated with the subtype of mEOC. KEGG pathway enrichment analysis showed genes in the turquoise module significantly enriched in metabolism of xenobiotics by cytochrome P450 and steroid hormone biosynthesis. Ten hub genes (LIPH, BCAS1, FUT3, ZG16B, PTPRH, SLC4A4, MUC13, TFF1, HNF4G and TFF2) in the turquoise module were validated to be highly expressed in mEOC using two independent gene expression datasets GSE44104 and GSE30274.
CONCLUSION: Our work proposed an applicable framework of molecular characteristics for patients with mEOC, which may help us to obtain a precise and comprehensive understanding on the molecular complexities of mEOC. The hub genes identified in our study, as potential specific biomarkers of mEOC, may be applied in the early diagnosis of mEOC in the future.

Wu Q, Zhang B, Wang Z, et al.
Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in gastric cancer.
Pathol Res Pract. 2019; 215(5):1038-1048 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: The underlying molecular mechanisms of gastric cancer (GC) have yet not been investigated clearly. In this study, we aimed to identify hub genes involved in the pathogenesis and prognosis of GC.
METHODS: We integrated five microarray datasets from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between GC and normal samples were analyzed with limma package. Gene ontology (GO) and KEGG enrichment analysis were performed using DAVID. Then we established the protein-protein interaction (PPI) network of DEGs by the Search Tool for the Retrieval of Interacting Genes database (STRING). The prognostic analysis of hub genes were performed through Gene Expression Profiling Interactive Analysis (GEPIA). Additionally, we used real-time quantitative PCR to validate the expression of hub genes in 5 pairs of tumor tissues and corresponding adjacent tissues. Finally, the candidate small molecules as potential drugs to treat GC were predicted in CMap database.
RESULTS: Through integrating five microarray datasets, a total of 172 overlap DEGs were detected including 79 up-regulated and 93 down-regulated genes. Biological process analysis of functional enrichment showed these DEGs were mainly enriched in digestion, collagen fibril organization and cell adhesion. Signaling pathway analysis indicated that these DEGs played an vital in ECM-receptor interaction, focal adhesion and metabolism of xenobiotics by cytochrome P450. Protein-protein interaction network among the overlap DEGs was established with 124 nodes and 365 interactions. Three DEGs with high degree of connectivity (NID2, COL4A1 and COL4A2) were selected as hub genes. The GEPIA database confirmed that overexpression levels of hub genes were significantly associated with worse survival of patients. Finally, the 20 most significant small molecules were obtained based on CMap database and spiradoline was the most promising small molecule to reverse the GC gene expression.
CONCLUSIONS: Our results indicated that NID2, COL4A1 and COL4A2 could be the potential novel biomarkers for GC diagnosis prognosis and the promising therapeutic targets. The present study may be crucial to understanding the molecular mechanism of GC initiation and progression.

Ye Z, Wang F, Yan F, et al.
Bioinformatic identification of candidate biomarkers and related transcription factors in nasopharyngeal carcinoma.
World J Surg Oncol. 2019; 17(1):60 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The incidence of nasopharyngeal carcinoma (NPC) is rare, but a certain amount of mortality remains in NPC patients. Our study aimed to identify candidate genes as biomarkers for NPC screening, diagnosis, and therapy.
METHODS: We investigated two microarray profile datasets GSE64634 and GSE12452 to screen the potential differentially expressed genes (DEGs) in NPC. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs were also performed. A protein-protein interaction (PPI) network of DEGs was constructed by STRING and visualized by Cytoscape software. The associated transcriptional factor regulatory network of the DEGs was also constructed.
RESULTS: A total of 152 DEGs were identified from the GSE64634 and GSE12452 datasets, including 10 upregulated and 142 downregulated genes. Gene functional enrichment analysis indicated that these DEGs were enriched in the cilium movement, antimicrobial humoral response, O-glycan processing, mucosal immune response, carbohydrate transmembrane transporter activity, hormone biosynthetic process, neurotransmitter biosynthetic process, and drug metabolism-cytochrome P450 pathway. Five hub genes (DNALI1, RSPH4A, RSPH9, DNAI2, and ALDH3A1) and one significant module (score = 5.6) were obtained from the PPI network. Key transcriptional factors, such as SPI1, SIN3B, and GATA2, were identified with close interactions with these five hub DEGs from the gene-transcriptional factor network.
CONCLUSIONS: With the integrated bioinformatic analysis, numerous DEGs related to NPC were screened, and the hub DEGs we identified may be potential biomarkers for NPC.

Wang JS, Wang YG, Zhong YS, et al.
Identification of co-expression modules and pathways correlated with osteosarcoma and its metastasis.
World J Surg Oncol. 2019; 17(1):46 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Osteosarcoma is the most common bone tumor that occurs in children.
METHODS: To identify co-expression modules and pathways correlated with osteosarcoma and its clinical characteristics, we performed weighted gene co-expression network analysis (WGCNA) on RNA-seq data of osteosarcoma with 52 samples. Then we performed pathway enrichment analysis on genes from significant modules.
RESULTS: A total of 5471 genes were included in WGCNA, and 16 modules were identified. Module-trait analysis identified that a module involved in microtubule bundle formation, drug metabolism-cytochrome P450, and IL-17 signaling pathway was negatively correlated with osteosarcoma and positively correlated with metastasis; a module involved in DNA replication was positively correlated with osteosarcoma; a module involved in cell junction was positively correlated with metastasis; and a module involved in heparin binding negatively correlated with osteosarcoma. Moreover, expression levels in four of the top ten differentially expressed genes were validated in another independent dataset.
CONCLUSIONS: Our analysis might provide insight for molecular mechanisms of osteosarcoma.

Lin JT, Chan TC, Li CF, et al.
Downregulation of the cytochrome P450 4B1 protein confers a poor prognostic factor in patients with urothelial carcinomas of upper urinary tracts and urinary bladder.
APMIS. 2019; 127(4):170-180 [PubMed] Related Publications
The objective of this study was to examine the expression level of cytochrome P450 4B1 (CYP4B1) protein and its clinical significance in specimens from patients with urothelial carcinomas (UC) including upper tract urothelial carcinoma (UTUC, n = 340) and urinary bladder urothelial carcinoma (UBUC, n = 295). Data mining on public domains identified five potential candidate transcripts which were downregulated in advanced UBUCs, indicating that it might implicate in UC progression. Immunohistochemistry was performed to analyze the CYP4B1 protein levels on 635 tissues from UC patients retrospectively. Immunoexpression of CYP4B1 was further estimated using the H-score method. Correlations between CYP4B1 H-score and important clinicopathological factors, as well as the significance of CYP4B1 expression level for disease-specific and metastasis-free survivals were evaluated. In UTUCs and UBUCs, 118 (34.7%) and 92 (31.2%) patients, respectively, were identified to be of CYP4B1 downregulation. The CYP4B1 expression level was found to be associated with several clinicopathological factors and patient survivals. Downregulation of CYP4B1 protein was correlated to advanced primary tumor (p < 0.001), nodal metastasis (p < 0.001), high histological grade (p = 0.001), vascular invasion (p < 0.001), perineural invasion (p = 0.017) and mitotic rate (p = 0.036) in UTUCs and/or UBUCs. Low CYP4B1 protein level independently predicted inferior disease-specific (p = 0.009; p < 0.001) and metastasis-free (p = 0.035; p < 0.001) survivals in UTUC and UBUC patients. Our findings showed that downregulation of CYP4B1 protein level is an independent unfavorable prognosticator. Loss of the CYP4B1 gene expression may play an important role in UC progression.

Yamaguchi M, Hankinson O
2,3,7,8‑tetrachlorodibenzo‑p‑dioxin suppresses the growth of human colorectal cancer cells in vitro: Implication of the aryl hydrocarbon receptor signaling.
Int J Oncol. 2019; 54(4):1422-1432 [PubMed] Free Access to Full Article Related Publications
Human colorectal cancer is the third most common cancer disease with a 5‑year survival rate of 55% in USA in 2016. The investigation to identify novel biomarker factors with molecular classification may provide notable clinical information to prolong the survival of patients with colorectal cancer. The aryl hydrocarbon receptor (AHR) binds the AHR nuclear translocator in the cytoplasm of various types of cells, including liver cells, and then binds to the xenobiotic responsive element on various genes. AHR was initially discovered via its ligand, the polychlorinated hydrocarbon, 2,3,7,8‑tetrachlorodibenzo‑p‑dioxin (TCDD). The present study was undertaken to determine whether TCDD, an agonist of AHR signaling, impacts the growth of RKO human colorectal cancer cells in vitro. Treatment with TCDD (0.1‑100 nM) revealed suppressive effects on colony formation and proliferation of RKO cells, and stimulated death of these cells with subconfluence. These effects of TCDD were abolished by pretreatment with CH223191, an inhibitor of AHR signaling. Western blot analysis demonstrated that TCDD treatment decreased AHR levels and elevated cytochrome P450 family 1 subfamily A member 1 (CYP1A1) levels, indicating a stimulation of AHR signaling. TCDD treatment caused an increase in nuclear factor‑κB p65 and β‑catenin levels, although it did not have an effect on Ras levels. Notably, TCDD treatment increased the levels of p53, retinoblastoma, p21 and regucalcin, which are depressors of carcinogenesis. Additionally, action of TCDD on cell proliferation and death were not revealed in regucalcin‑overexpressing RKO cells, and regucalcin overexpression depressed AHR signaling associated with CYP1A1 expression. Thus, AHR signaling suppresses the growth of colorectal cancer cells, indicating a role as a significant targeting molecule for colorectal cancer.

Zhou YX, Fuentes-Creollo G, Ponce F, et al.
No difference in 4-nitroquinoline induced tumorigenesis between germ-free and colonized mice.
Mol Carcinog. 2019; 58(5):627-632 [PubMed] Related Publications
Variations in oral bacterial communities have been linked to oral cancer suggesting that the oral microbiome is an etiological factor that can influence oral cancer development. The 4-nitroquinoline 1-oxide (4-NQO)-induced murine oral and esophageal cancer model is frequently used to assess the effects of preventive and/or therapeutic agents. We used this model to assess the impact of the microbiome on tumorigenesis using axenic (germ-free) and conventionally housed mice. Increased toxicity was observed in germ-free mice, however, no difference in tumor incidence, multiplicity, and size was observed. Transcriptional profiling of liver tissue from germ-free and conventionally housed mice identified 254 differentially expressed genes including ten cytochrome p450 enzymes, the largest family of phase-1 drug metabolizing enzymes in the liver. Gene ontology revealed that differentially expressed genes were enriched for liver steatosis, inflammation, and oxidative stress in livers of germ-free mice. Our observations emphasize the importance of the microbiome in mediating chemical toxicity at least in part by altering host gene expression. Studies on the role of the microbiome in chemical-induced cancer using germ-free animal models should consider the potential difference in dose due to the microbiome-mediated changes in host metabolizing capacity, which might influence the ability to draw conclusions especially for tumor induction models that are dose dependent.

Qi Y, Wang L, Wang K, et al.
New mechanistic insights of clear cell renal cell carcinoma from integrated miRNA and mRNA expression profiling studies.
Biomed Pharmacother. 2019; 111:821-834 [PubMed] Related Publications
Differentially expressed (DE) microRNAs (miRNAs) in clear cell renal cell carcinoma (ccRCC) tissues from pooled samples were reported to affect the tumorigenesis and progression of ccRCC. However, systematic studies on the miRNA-mRNA regulatory networks involved in various pathways in all four stages of the disease are lacking. In this study, we applied microarray technology to perform an integrated analysis of the miRNome and transcriptome in ccRCC tissues from patients at different stages of ccRCC. A total of 604 DEmiRNAs and 6892 DEgenes (DEGs) were identified by comparison with corresponding adjacent normal tissues. The pairing of miRNAs with DEGs were searched using validated miRWalk module, and the pairs were confirmed by comparing with DEmiRNAs in our study. Our results demonstrated that different stages of ccRCC had distinct miRNA/mRNA profiles. However, four common pathways (the complement and coagulation cascades, the pathway for the metabolism of xenobiotics by cytochrome P450, the PPAR signaling pathway, and the pathway for aldosterone-regulated sodium reabsorption) were enriched by targets of DEmiRNAs at all stages of ccRCC. We carried out an extensive analysis of data on miR-16, which had the most target genes, and found that its differential expression was validated in The Cancer Genome Atlas dataset. We also verified the correlation between miR-16 expression and target pathways by gene set enrichment analysis and in vitro experiments. High miR-16 level was also associated with shorter survival time in ccRCC. Our work presents a systematic profiling of miRNA, mRNA and pathways regulated by miRNAs in different stages of ccRCC. Our cross-omics results also identify four common pathways that function aberrantly in all stages of the disease. These pathways are likely to be critical in occurrence and progression of ccRCC. These common dysfunctional pathways have the potential to serve as therapeutic targets and diagnostic biomarkers, whereas miRNAs (miR-20, 484, 497) differentially expressed in only stage I tissues and in blood could be used to diagnose early-stage ccRCC patients.

Qiu J, Du Z, Liu J, et al.
Association between polymorphisms in estrogen metabolism genes and breast cancer development in Chinese women: A prospective case-control study.
Medicine (Baltimore). 2018; 97(47):e13337 [PubMed] Free Access to Full Article Related Publications
We comprehensively identified polymorphisms in estrogen-metabolizing genes that may be associated with breast cancer initiation in Chinese women, via an ongoing prospective case-control study.An ongoing prospective case-control study of 427 female case patients diagnosed with breast cancer from August 2013 to March 2015 and 536 women (case controls) with no prior history of cancer or benign breast tumors was performed. Buccal cell specimens were obtained using the cotton swabbing method. DNA was extracted from the buccal cells using the phenol/chloroform method. Genotype was carried out for 5 single nucleotide polymorphisms (rs4646903, rs1056836, rs1695, rs4970737, and rs4680) using direct sequencing.The polymorphic genotypes of glutathione S-transferase (GSTP1) (P = .044) and catechol-O-methyltransferase (COMT) (P = .008) showed significantly different distributions, while that of cytochrome P450 (CYP1B1) (P = .051) showed a slight difference in distribution between healthy women and patients with breast cancer. Individuals with homozygous variant genotypes for GSTP1 or COMT exhibited a higher risk of developing breast cancer than those with wild-type genotypes; however, for CYP1B1, the homozygous variant genotype was associated with a lower risk, and the heterozygous genotype for these 3 genes was not associated with breast cancer development.An individual's risk of breast cancer is only influenced by the specific combination of risk-associated alleles of COMT and GSTP1, despite the protective effects of the homozygous CYP1B1 genotype revealed by univariate analysis.

Ruiz-Pinto S, Martin M, Pita G, et al.
Pharmacogenetic variants and response to neoadjuvant single-agent doxorubicin or docetaxel: a study in locally advanced breast cancer patients participating in the NCT00123929 phase 2 randomized trial.
Pharmacogenet Genomics. 2018; 28(11):245-250 [PubMed] Related Publications
OBJECTIVES: Taxanes and anthracyclines are widely used in the treatment of breast cancer, although the benefit is limited to a proportion of patients and predictive biomarkers for clinical outcome remain elusive.
PATIENTS AND METHODS: We carried out a pharmacogenetic study in 181 patients with locally advanced breast cancer enrolled in a phase 2 randomized clinical trial (NCT00123929), where patients were randomly assigned to receive neoadjuvant single-agent docetaxel 100 mg/m(2) (n=84) or doxorubicin 75 mg/m(2) (n=97). We studied the association of 226 single nucleotide polymorphisms (SNPs) in 15 key drug biotransformation genes with neoadjuvant pathological tumor response residual cancer burden index to docetaxel and to doxorubicin.
RESULTS: We identified a significant association for rs162561, an intronic SNP located in the cytochrome P450 family 1 subfamily B member 1 (CYP1B1) gene, with tumor response in patients treated with single-agent docetaxel (dominant model: β=1.02, 95% confidence interval=0.49-1.55; P=1.77×10(-4)), and for rs717620, an SNP located in the promoter of the ATP-binding cassette subfamily C member 2 (ABCC2) gene, in patients treated with neoadjuvant doxorubicin (recessive model: β=1.67; 95% confidence interval=0.26-3.11; P=0.02).
CONCLUSION: We identified two polymorphisms in CYP1B1 and ABCC2 associated with tumor pathological response following docetaxel or doxorubicin neoadjuvant monotherapy, respectively. Although further validation is required, these variants could be potential predictive genetic markers for treatment outcome in breast cancer patients.

Eun HS, Cho SY, Lee BS, et al.
Profiling cytochrome P450 family 4 gene expression in human hepatocellular carcinoma.
Mol Med Rep. 2018; 18(6):4865-4876 [PubMed] Free Access to Full Article Related Publications
Cytochrome P450 family 4 (CYP4) enzymes are known as microsomal omega (ω)-hydroxylases that metabolize fatty acids, eicosanoids, vitamin D and carcinogens. Thus, CYP4 enzymes may influence tumor development and progression. The aim of the present study was to evaluate the CYP4 expression profile in hepatocellular carcinoma (HCC) and its clinical relevance. The present study obtained CYP4 mRNA expression data for 377 HCC cases from The Cancer Genome Atlas cohort and performed Kaplan‑Meier survival, Gene Ontology functional enrichment, and gene set enrichment analysis (GSEA). In addition, the level of CYP4F2 protein expression was evaluated in matched pairs of HCC and non‑tumor tissue samples and the results were correlated with the clinicopathological characteristics of HCC (n=113). HCC survival analyses indicated better overall survival in patients with high CYP4F2, CYP4F12 and CYP4V2 mRNA expression levels; the results for histological grade and Tumor‑Node‑Metastasis stage supported these results. GSEA revealed high levels of CYP4F2, CYP4F12 and CYP4V2 mRNA expression to be negatively correlated with the expression of cell cycle‑associated genes. CYP4F2 protein expression was higher in non‑neoplastic liver tissue than in HCC tissue and positively correlated with favorable pathological tumor stage (I vs. II‑IV; P=0.022) and was a good independent prognostic factor for overall survival (P=0.004). These results demonstrate that the expression levels of the genes CYP4F2, CYP4F12 and CYPV2 are favorable prognostic factors in HCC and suggest the potential predictive diagnostic and prognostic roles of CYP4F2, CYP4F12 and CYPV2 gene expression in HCC.

Yin X, Xiong W, Wang Y, et al.
Association of CYP2E1 gene polymorphisms with bladder cancer risk: A systematic review and meta-analysis.
Medicine (Baltimore). 2018; 97(39):e11910 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human cytochrome P450 (CYP) is an enzyme responsible for the metabolic activation of many carcinogens, including nitrosamines. CYP2E1 represents a major CYP isoform and is expressed in the human urothelial cells. Recent studies have investigated the association of CYP2E1 gene polymorphisms with bladder cancer risk but have shown contradictory results. Hence, we performed a systematic literature review and meta-analysis to assess the association between CYP2E1 gene polymorphisms and bladder cancer.
METHODS: Systematic literature searches were conducted with PubMed, Excerpt Medica Database, Science Direct/Elsevier, China National Knowledge Infrastructure, and the Cochrane Library up to January 2018 for studies that involved the association of CYP2E1 gene polymorphisms with bladder cancer risk. A meta-analysis was performed with Review Manager and Stata software. Combined odds ratios (ORs) were identified with 95% confidence intervals (CIs) in a random or fixed effects model.
ETHICS: The protocol was approved by the institutional review board of each study center. Written informed consent will be obtained from all patients before registration, in accordance with the Declaration of Helsinki.
RESULTS: Eight studies were identified, including 1733 cases of bladder cancer and 1814 normal controls. Our results illustrated that there are significant associations between CYP2E1 gene polymorphisms and bladder cancer in all genetic models (P < .05). The combined ORs and 95% CIs were as follows for each model: additive model [OR 0.56; 95% CI (0.38-0.82)]; dominant model [OR 0.79; 95% CI (0.67-0.93)]; recessive model [OR 0.61; 95% CI (0.41-0.89)]; codominant model [OR 0.80; 95% CI (0.67-0.96)]; allele model [OR 0.75; 95% CI (0.59-0.95)]. A subgroup study showed that there are also significant associations between CYP2E1 gene polymorphisms and bladder cancer in Asian people. However, there are no significant associations between CYP2E1 gene polymorphisms and bladder cancer in Caucasian populations.
CONCLUSIONS: The present study provides evidence for an association between CYP2E1 gene polymorphisms and bladder cancer progression, and suggests that CYP2E1 gene polymorphisms might be a protective factor against bladder cancer in Asian people. However, studies with larger sample sizes are needed to confirm the correlation between CYP2E1 gene polymorphisms and bladder cancer.

Mazzio EA, Soliman KFA
Whole-transcriptomic Profile of SK-MEL-3 Melanoma Cells Treated with the Histone Deacetylase Inhibitor: Trichostatin A.
Cancer Genomics Proteomics. 2018 Sep-Oct; 15(5):349-364 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Malignant melanoma cells can rapidly acquire phenotypic properties making them resistant to radiation and mainline chemotherapies such as decarbonize or kinase inhibitors that target RAS-proto-oncogene independent auto-activated mitogen-activated protein kinases (MAPK)/through dual specificity mitogen-activated protein kinase (MEK). Both drug resistance and inherent transition from melanocytic nevi to malignant melanoma involve the overexpression of histone deacetylases (HDACs) and a B-Raf proto-oncogene (BRAF) mutation.
MATERIALS AND METHODS: In this work, the effects of an HDAC class I and II inhibitor trichostatin A (TSA) on the whole transcriptome of SK-MEL-3 cells carrying a BRAF mutation was examined.
RESULTS: The data obtained show that TSA was an extremely potent HDAC inhibitor within SK-MEL-3 nuclear lysates, where TSA was then optimized for appropriate sub-lethal concentrations for in vitro testing. The whole-transcriptome profile shows a basic phenotype dominance in the SK-MEL-3 cell line for i) synthesis of melanin, ii) phagosome acidification, iii) ATP hydrolysis-coupled proton pumps and iv) iron transport systems. While TSA did not affect the aforementioned major systems, it evoked a dramatic change to the transcriptome: reflected by a down-regulation of 810 transcripts and up-regulation of 833, with fold-change from -15.27 to +31.1 FC (p<0.00001). Largest differentials were found for the following transcripts: Up-regulated: Tetraspanin 13 (TSPAN13), serpin family i member 1 (SERPINI1), ATPase Na+/K+ transporting subunit beta 2 (ATP1B2), nicotinamide nucleotide adenylyl transferase 2 (NMNAT2), platelet-derived growth factor receptor-like (PDGFRL), cytochrome P450 family 1 subfamily A member 1 (CYP1A1), prostate androgen-regulated mucin-like protein 1 (PARM1), secretogranin II (SCG2), SYT11 (synaptotagmin 11), rhophilin associated tail protein 1 like (ROPN1L); down-regulated: polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), carbonic anhydrase 14 (CAXIV), BCL2-related protein A1 (BCL2A1), protein kinase C delta (PRKCD), transient receptor potential cation channel subfamily M member 1 (TRPM1), ubiquitin associated protein 1 like (UBAP1L), glutathione peroxidase 8 (GPX8), interleukin 16 (IL16), tumor protein p53 (TP53), and serpin family H member 1 (SERPINH1). There was no change to any of the HDAC transcripts (class I, II and IV), the sirtuin HDAC family (1-6) or the BRAF proto-oncogene v 599 transcripts. However, the data showed that TSA down-regulated influential transcripts that drive the BRAF-extracellular signal-regulated kinase (ERK)1/2 oncogenic pathway (namely PRKCD and MYC proto-oncogene which negatively affected the cell-cycle distribution. Mitotic inhibition was corroborated by functional pathway analysis and flow cytometry confirming halt at the G
CONCLUSION: TSA does not alter HDAC transcripts nor BRAF itself, but down-regulates critical components of the MAPK/MEK/BRAF oncogenic pathway, initiating a mitotic arrest.

Elfaki I, Mir R, Almutairi FM, Duhier FMA
Cytochrome P450: Polymorphisms and Roles in Cancer, Diabetes and Atherosclerosis
Asian Pac J Cancer Prev. 2018; 19(8):2057-2070 [PubMed] Free Access to Full Article Related Publications
Cytochromes P450s (CYPs) constitute a superfamily of enzymes that catalyze the metabolism of drugs and other substances. Endogenous substrates of CYPs include eicosanoids, estradiol, arachidonic acids, cholesterol, vitamin D and neurotransmitters. Exogenous substrates of CYPs include the polycyclic aromatic hydrocarbons and about 80% of currently used drugs. Some isoforms can activate procarcinogens to ultimate carcinogens. Genetic polymorphisms of CYPs may affect the enzyme catalytic activity and have been reported among different populations to be associated with various diseases and adverse drug reactions. With regard of drug metabolism, phenotypes for CYP polymorphism range from ultrarapid to poor metabolizers. In this review, we discuss some of the most clinically important CYPs isoforms (CYP2D6, CYP2A6, CYP2C19, CYP2C9, CYP1B1 and CYP1A2) with respect to gene polymorphisms and drug metabolism. Moreover, we review the role of CYPs in renal, lung, breast and prostate cancers and also discuss their significance for atherosclerosis and type 2 diabetes mellitus.

Pedersen MH, Hood BL, Ehmsen S, et al.
CYPOR is a novel and independent prognostic biomarker of recurrence-free survival in triple-negative breast cancer patients.
Int J Cancer. 2019; 144(3):631-640 [PubMed] Related Publications
Prognostic and predictive biomarkers of disease and treatment outcome are needed to ensure optimal treatment of patients with triple-negative breast cancer (TNBC). In a mass spectrometry-based global proteomic study of 44 formalin-fixed, paraffin-embedded (FFPE) primary TNBC tumors and 10 corresponding metastases, we found that Cytochrome P450 reductase (CYPOR) expression correlated with patient outcome. The correlation between CYPOR expression and outcome was further evaluated in a Danish cohort of 113 TNBC patients using immunohistochemistry and publicly available gene expression data from two cohorts of TNBC and basal-like breast cancer patients, respectively (N = 249 and N = 580). A significant correlation between high CYPOR gene expression and shorter recurrence-free survival (RFS), but not overall survival, was found in the cohort of 249 TNBC patients (p = 0.018, HR = 1.77, 95% CI 1.1-2.85), and this correlation was recapitulated in a cohort of 580 basal-like breast cancer patients (p = 0.018, HR = 1.4, 95% CI 1.06-1.86). High CYPOR protein expression was also associated with shorter RFS in the cohort of 113 TNBC patients (p = 0.017, HR = 2.73, 95% CI 1.20-6.19), particularly those who were lymph node tumor-negative (p = 0.029, HR = 5.22). Multivariate Cox regression analysis identified CYPOR as an independent prognostic factor for shorter RFS in TNBC patients (p = 0.032, HR = 2.19, 95% CI 1.07-4.47). Together, these data suggest high expression of CYPOR as an independent prognostic biomarker of shorter RFS, which could be used to identify patients who should receive more extensive adjuvant treatment and more aggressive surveillance.

Dong Q, Lv C, Zhang G, et al.
Impact of RNA‑binding motif 3 expression on the whole transcriptome of prostate cancer cells: An RNA sequencing study.
Oncol Rep. 2018; 40(4):2307-2315 [PubMed] Related Publications
RNA‑binding motif 3 (RBM3) is a cold‑shock protein that has been previously shown to attenuate cancer stem cell‑like features in prostate cancer (PCa) cells. However, the mechanism underlying RBM3 regulation in PCa cells is largely unknown. The present study investigated the impact of RBM3 expression on the whole transcriptome of PCa cells using high‑throughput RNA sequencing (RNA‑seq). Differentially expressed genes (DEGs) that were identified through RNA‑seq were applied to Gene Ontology (GO), pathway analysis, pathway‑action networks and protein‑protein interaction network analysis. GO and pathway ananlyses showed that RBM3 expression was associated with several metabolism pathways. Combining GO analysis and pathway analysis, certain DEGs, including phospholipase A2 group IIA (PLA2G2A), PLA2G2F, PLA2G4C, endothelin 1, cytochrome P450 family 2 subfamily B member 6, G protein subunit γ5, nitric oxide synthase 3 and CD38 molecule, were shown to be closely associated with RBM3 regulation in PCa cells. Furthermore, the changes in expression of selected genes upon RBM3‑knockdown in RNA‑seq were confirmed by separate reverse transcription‑quantitative‑polymerase chain reaction, validating the results of RNA‑seq. Thus, the present study provides a series of valuable reference genes and pathways for the future study of the pathogenic role of RBM3 in the development of PCa.

Bulus H, Oguztuzun S, Güler Simsek G, et al.
Expression of CYP and GST in human normal and colon tumor tissues.
Biotech Histochem. 2019; 94(1):1-9 [PubMed] Related Publications
We investigated the immunohistochemical staining characteristics of cytochrome P450 1A1 (CYP1A1), CYPB1, CYP2E1, and glutathione S-transferase P1 (GSTP1), GSTT1, GSTO1, GSTK1 in colon tumor and surrounding normal colon tissues. Tissues were obtained from 47 patients with colon adenocarcinoma and the staining intensity of tumor and control tissues was compared. CYP1A1, CYP1B1, CYP2E1, GSTP1, GSTT1, GSTO1 and GSTK1 expressions in colon cancer cells were significantly greater than those in normal colon epithelial cells. No significant relation was found between the isoenzyme expressions and age, gender, smoking status, tumor grade and tumor stage. The higher expressions of CYP1A1, CYP1B1, CYP2E1, GSTP1, GSTO1, GSTT1 and GSTK1 in tumor than in normal colon tissues may be important for colon cancer progression and development.

Eun HS, Cho SY, Lee BS, et al.
Cytochrome P450 4A11 expression in tumor cells: A favorable prognostic factor for hepatocellular carcinoma patients.
J Gastroenterol Hepatol. 2019; 34(1):224-233 [PubMed] Related Publications
BACKGROUND AND AIM: Elevated cytochrome p450 (CYP) 4A gene expression has been linked to the aggravation of various cancers and affects various regulated metabolites. In hepatocellular carcinoma (HCC), the clinicopathological value of CYP4A has not yet been explored, although CYP4A is expressed at high levels in the liver. The goal of this study was to evaluate the clinicopathological value of CYP4A11 expression in HCC.
METHODS: We performed immunohistochemical analysis of CYP4A11 and correlated the results with clinicopathological features of HCC (n = 155). Western blotting and reverse transcription-polymerase chain reaction against CYP4A11 and CYP4A22 were also performed for 15 and 20 pairs of fresh-frozen primary HCC and non-neoplastic liver tissue, respectively. Moreover, we analyzed the underlying mechanism by comparing the high and low CYP4A11 mRNA expression groups using gene set enrichment analysis.
RESULTS: CYP4A11 expression level was higher in non-neoplastic hepatocytes than those in HCC cells (P < 0.001), and CYP4A11 expression positively correlated with favorable prognostic factors, including tumor size, histological grade, and pathological tumor stage (P = 0.007, P = 0.005, and P = 0.007). Multivariate analysis revealed that CYP4A11 expression was an independent prognostic factor of overall and disease-free survival (P = 0.002 and P = 0.033). Based on gene set enrichment analysis, high CYP4A11 mRNA expression negatively correlated with the expression of cell cycle-related genes.
CONCLUSION: These findings support the notion that CYP4A11 expression is a favorable prognostic factor of HCC and suggest potential predictive diagnostic and prognostic roles of CYP4A11 expression in HCC.

Cheng L, Li L, Wang L, et al.
A random forest classifier predicts recurrence risk in patients with ovarian cancer.
Mol Med Rep. 2018; 18(3):3289-3297 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer (OC) is associated with a poor prognosis due to difficulties in early detection. The aims of the present study were to construct a recurrence risk prediction model and to reveal important OC genes or pathways. RNA sequencing data was obtained for 307 OC samples, and the corresponding clinical data were downloaded from The Cancer Genome Atlas database. Additionally, two validation datasets, GSE44104 (20 recurrent and 40 non‑recurrent OC samples) and GSE49997 (204 OC samples), were obtained from the Gene Expression Omnibus database. Differentially expressed genes were screened using the differential expression via distance synthesis algorithm, followed by gene ontology enrichment analysis and weighted gene coexpression network analysis (WGCNA). Furthermore, subnetwork analysis was conducted for the protein‑protein interaction (PPI) network using the BioNet package. Finally, a random forest classifier was constructed based on the subnetwork nodes, and its reliability was validated using the GSE44104 and GSE49997 validation datasets. A total of 44 upregulated and 117 downregulated genes were identified in the recurrent samples. Enrichment analysis indicated that cytochrome P450 family 17 subfamily A member 1 (CYP17A1) was associated with 'positive regulation of steroid hormone biosynthetic processes'. WGCNA identified turquoise and grey modules that were significantly correlated with status and prognosis. A significant PPI subnetwork containing 16 nodes was also identified, including: Transcription factor GATA‑4; fibroblast growth factor 9; aromatase; 3β‑hydroxysteroid dehydrogenase/δ5‑4‑isomerase type 2; corticosteroid 11β‑dehydrogenase isozyme 1; CYP17A1; pituitary homeobox 2; left‑right determination factor 1; homeobox protein ARX; estrogen receptor β; steroidogenic factor 1; forkhead box protein L2; myocardin; steroidogenic acute regulatory protein mitochondrial; vesicular inhibitory amino acid transporter; and twist‑related protein 1. A random forest classifier was constructed using the subnetwork nodes as feature genes, which exhibited a 92% true positive rate when classifying recurrent and non‑recurrent OC samples. The classifying efficiency of the random forest classifier was validated using the two other independent datasets. Overall, 44 upregulated and 117 downregulated genes associated with OC recurrence were identified. Furthermore, the 16 subnetwork node genes that were identified may be important molecules in OC recurrence.

Simigdala N, Pancholi S, Ribas R, et al.
Abiraterone shows alternate activity in models of endocrine resistant and sensitive disease.
Br J Cancer. 2018; 119(3):313-322 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Resistance to endocrine therapy remains a major clinical problem in the treatment of oestrogen-receptor positive (ER+) breast cancer. Studies show androgen-receptor (AR) remains present in 80-90% of metastatic breast cancers providing support for blockade of AR-signalling. However, clinical studies with abiraterone, which blocks cytochrome P450 17A1 (CYP17A1) showed limited benefit.
METHODS: In order to address this, we assessed the impact of abiraterone on cell-viability, cell-death, ER-mediated transactivation and recruitment to target promoters. together with ligand-binding assays in a panel of ER+ breast cancer cell lines that were either oestrogen-dependent, modelling endocrine-sensitive disease, or oestrogen-independent modelling relapse on an aromatase inhibitor. The latter, harboured wild-type (wt) or naturally occurring ESR1 mutations.
RESULTS: Similar to oestrogen, abiraterone showed paradoxical impact on proliferation by stimulating cell growth or death, depending on whether the cells are hormone-dependent or have undergone prolonged oestrogen-deprivation, respectively. Abiraterone increased ER-turnover, induced ER-mediated transactivation and ER-degradation via the proteasome.
CONCLUSIONS: Our study confirms the oestrogenic activity of abiraterone and highlights its differential impact on cells dependent on oestrogen for their proliferation vs. those that are ligand-independent and harbour wt or mutant ESR1. These properties could impact the clinical efficacy of abiraterone in breast cancer.

Molehin D, Castro-Piedras I, Sharma M, et al.
Aromatase Acetylation Patterns and Altered Activity in Response to Sirtuin Inhibition.
Mol Cancer Res. 2018; 16(10):1530-1542 [PubMed] Related Publications
Aromatase, a cytochrome P450 member, is a key enzyme involved in estrogen biosynthesis and is dysregulated in the majority of breast cancers. Studies have shown that lysine deacetylase inhibitors (KDI) decrease aromatase expression in cancer cells, yet many unknowns remain regarding the mechanism by which this occurs. However, advances have been made to clarify factors involved in the transcriptional regulation of the aromatase gene (

Andersen ME, Cruzan G, Black MB, et al.
Strain-related differences in mouse lung gene expression over a two-year period of inhalation exposure to styrene: Relevance to human risk assessment.
Regul Toxicol Pharmacol. 2018; 96:153-166 [PubMed] Related Publications
Both CD-1 and C57BL/6 wildtype (C57BL/6-WT) mice show equivalent short-term lung toxicity from exposures to styrene, while long-term tumor responses are greater in CD-1 mice. We analyzed lung gene expression from styrene exposures lasting from 1-day to 2-years in male mice from these two strains, including a Cyp2f2(-/-) knockout (C57BL/6-KO) and a Cyp2F1/2A13/2B6 transgenic mouse (C57BL/6-TG). With short term exposures (1-day to 1-week), CD-1 and C57BL/6-WT mice had thousands of differentially expressed genes (DEGs), consistent with changes in pathways for cell proliferation, cellular lipid metabolism, DNA-replication and inflammation. C57BL/6-WT mice responded within a single day; CD-1 mice required several days of exposure. The numbers of exposure related DEGs were greatly reduced at longer times (4-weeks to 2-years) with enrichment only for biological oxidations in C57BL/6-WT and metabolism of lipids and lipoproteins in CD-1. Gene expression results indicate a non-genotoxic, mouse specific mode of action for short-term styrene responses related to activation of nuclear receptor signaling and cell proliferation. Greater tumor susceptibility in CD-1 mice correlated with the presence of the Pas1 loci, differential Cytochrome P450 gene expression, down-regulation of Nr4a, and greater inflammatory pathway activation. Very few exposure-related responses occurred at any time in C57BL/6-KO or -TG mice indicating that neither the short term nor long term responses of styrene in mice are relevant endpoints for assessing human risks.

Chen S, Fan X, Gu H, et al.
Competing endogenous RNA regulatory network in papillary thyroid carcinoma.
Mol Med Rep. 2018; 18(1):695-704 [PubMed] Free Access to Full Article Related Publications
The present study aimed to screen all types of RNAs involved in the development of papillary thyroid carcinoma (PTC). RNA‑sequencing data of PTC and normal samples were used for screening differentially expressed (DE) microRNAs (DE‑miRNAs), long non‑coding RNAs (DE‑lncRNAs) and genes (DEGs). Subsequently, lncRNA‑miRNA, miRNA‑gene (that is, miRNA‑mRNA) and gene‑gene interaction pairs were extracted and used to construct regulatory networks. Feature genes in the miRNA‑mRNA network were identified by topological analysis and recursive feature elimination analysis. A support vector machine (SVM) classifier was built using 15 feature genes, and its classification effect was validated using two microarray data sets that were downloaded from the Gene Expression Omnibus (GEO) database. In addition, Gene Ontology function and Kyoto Encyclopedia Genes and Genomes pathway enrichment analyses were conducted for genes identified in the ceRNA network. A total of 506 samples, including 447 tumor samples and 59 normal samples, were obtained from The Cancer Genome Atlas (TCGA); 16 DE‑lncRNAs, 917 DEGs and 30 DE‑miRNAs were screened. The miRNA‑mRNA regulatory network comprised 353 nodes and 577 interactions. From these data, 15 feature genes with high predictive precision (>95%) were extracted from the network and were used to form an SVM classifier with an accuracy of 96.05% (486/506) for PTC samples downloaded from TCGA, and accuracies of 96.81 and 98.46% for GEO downloaded data sets. The ceRNA regulatory network comprised 596 lines (or interactions) and 365 nodes. Genes in the ceRNA network were significantly enriched in 'neuron development', 'differentiation', 'neuroactive ligand‑receptor interaction', 'metabolism of xenobiotics by cytochrome P450', 'drug metabolism' and 'cytokine‑cytokine receptor interaction' pathways. Hox transcript antisense RNA, miRNA‑206 and kallikrein‑related peptidase 10 were nodes in the ceRNA regulatory network of the selected feature gene, and they may serve import roles in the development of PTC.

Tan YQ, Chiu-Leung LC, Lin SM, Leung LK
The citrus flavonone hesperetin attenuates the nuclear translocation of aryl hydrocarbon receptor.
Comp Biochem Physiol C Toxicol Pharmacol. 2018; 210:57-64 [PubMed] Related Publications
The environmental polycyclic aromatic hydrocarbons (PAH) and dioxins are carcinogens and their adverse effects have been largely attributed to the activation of AhR. Hesperetin is a flavonone found abundantly in citrus fruits and has been shown to be a biologically active agent. In the present study, the effect of hesperetin on the nuclear translocation of AhR and the downstream gene expression was investigated in MCF-7 cells. Confocal microscopy indicated that 7, 12-dimethylbenz[α]anthracene (DMBA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) -induced nuclear translocation of AhR was deterred by hesperetin treatment. The reduced nuclear translocation could also be observed in Western analysis. Reporter-gene assay further illustrated that the induced XRE transactivation was weakened by the treatment of hesperetin. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay demonstrated that the gene expressions of CYP1A1, 1A2, and 1B1 followed the same pattern of AhR translocation. These results suggested that hesperetin counteracted AhR transactivation and suppressed the downstream gene expression.

Park JW, Lee CM, Cheng JS, Morgan ET
Posttranslational regulation of CYP2J2 by nitric oxide.
Free Radic Biol Med. 2018; 121:149-156 [PubMed] Free Access to Full Article Related Publications
Nitric oxide (NO) is an essential signaling molecule in the body, regulating numerous biological processes. Beside its physiological roles, NO affects drug metabolism by modulating the activity and/or expression of cytochrome P450 enzymes. Previously, our lab showed that NO generation caused by inflammatory stimuli results in CYP2B6 degradation via the ubiquitin-proteasome pathway. In the current study, we tested the NO-mediated regulation of CYP2J2 that metabolizes arachidonic acids to bioactive epoxyeicosatrienoic acids, as well as therapeutic drugs such as astemizole and ebastine. To investigate the effects of NO on CYP2J2 expression and activity, Huh7 cells stably transduced with CYP2J2 with a C-terminal V5 tag were treated with dipropylenetriamine-NONOate (DPTA), a NO donor. The level of CYP2J2 proteins were decreased in a time- and concentration-dependent manner, and the activity was also rapidly inhibited. However, mRNA expression was not altered and the protein synthesis inhibitor cycloheximide did not attenuate DPTA-mediated downregulation of CYP2J2. Removal of DPTA from the culture media quickly restored the activity of remaining CYP2J2, and no further CYP2J2 degradation occurred. To determine the mechanism of CYP2J2 down-regulation by NO, cells were treated with DPTA in the presence or absence of protease inhibitors including proteasomal, lysosomal and calpain inhibitors. Remarkably, the down-regulation of CYP2J2 by NO was attenuated by calpeptin, a calpain inhibitor. However, other calpain inhibitors or calcium chelator show no inhibitory effects on the degradation. The proteasome inhibitor bortezomib showed small but significant restoration of CYP2J2 levels although stimulated ubiquitination of CYP2J2 was not detected. In conclusion, these data suggest that NO regulates CYP2J2 posttranslationally and NO-evoked CYP2J2 degradation undergoes ubiquitin-independent proteasomal degradation pathway unlike CYP2B6.

Liu L, Chen F, Xiu A, et al.
Identification of Key Candidate Genes and Pathways in Endometrial Cancer by Integrated Bioinformatical Analysis
Asian Pac J Cancer Prev. 2018; 19(4):969-975 [PubMed] Free Access to Full Article Related Publications
Endometrial Cancer is the most common female genital tract malignancy, its pathogenesis is complex, not yet fully described. To identify key genes of Endometrial Cancer we downloaded the gene chip GSE17025 from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified through the GEO2R analysis tool. Functional and pathway enrichment analysis were performed for DEGs using DAVID database. The network of protein–protein-interaction (PPI) was established by STRING website and visualized by Cytoscape. Then, functional and pathway enrichment analysis of DEGS were performed by DAVID database. A total of 1000 significant differences genes were obtained, contain 362 up-regulated genes and 638 down-regulated genes. PCDH10, SLC6A2, OGN, SFRP4, TRH, ANGPTL, FOSB are down-regulated genes. The gene of IGH, CCL20, ELF5, LTF, ASPM expression level in tumor patients are up-regulated. Biological function of enrichment include metabolism of xenobiotics by cytochrome P450, MAPK signaling pathway, Serotonergic synapse, Protein digestion and absorption, IL-17 signaling pathway, Chemokine signaling pathway, HIF-1 signaling pathway, p53 signaling pathway. All in all, the current study to determine endometrial differentially expressed genes and biological function, comprehensive analysis of intrauterine membrane carcinoma pathogenesis mechanism, and might be used as molecular targets and diagnostic biomarkers for the treatment of endometrial cancer.

Moghadam AR, Mehramiz M, Entezari M, et al.
A genetic polymorphism in the CYP1B1 gene in patients with squamous cell carcinoma of the esophagus: an Iranian Mashhad cohort study recruited over 10 years.
Pharmacogenomics. 2018; 19(6):539-546 [PubMed] Related Publications
AIM: Esophageal cancer is the eighth most common cancer globally and the seventh most common cause of cancer-related deaths in men. Recent studies have shown that CYP450, family 1, subfamily B, polypeptide 1, which plays a role in the metabolism of xenobiotics, is associated with several cancers. Therefore, in the present study we investigated the association between a genetic variant, CYP1B1-rs1056836 gene, with the clinical characteristics of patients with squamous cell carcinoma of the esophagus (ESCC).
METHOD: In this study, 117 patients with ESCC and 208 healthy controls were recruited. DNA was extracted and genotyped using real-time PCR-based TaqMan. Kaplan-Meier curves were utilized to assess overall and progression-free survival. To evaluate the relationship between clinicopathological data, genotypic frequencies, disease prognosis and survival, Pearson's χ
RESULTS: The genotypic frequency for GG, GC and CC were 58.6, 29.8 and 11.5%, respectively, in the healthy subjects and 51.8, 36.14 and 12% in the ESCC group. An association between the GG genotype and stage of ESCC was found. Also, statistically significant results were not found for this variation and risk of ESCC.
CONCLUSION: Our findings suggest a relationship between the CYP1B1-rs1056836 genetic polymorphism and clinical features of ESCC, supporting further studies in larger populations in different ethnic groups, taking into account potentially important environmental factors such as diet.

Feng Y, Shi J, Jiao Z, et al.
Mechanism of bisphenol AF-induced progesterone inhibition in human chorionic gonadotrophin-stimulated mouse Leydig tumor cell line (mLTC-1) cells.
Environ Toxicol. 2018; 33(6):670-678 [PubMed] Related Publications
Bisphenol AF (BPAF) has been shown to inhibit testicular steroidogenesis in male rats. However, the precise mechanisms related to the toxic effects of BPAF on reproduction remain poorly understood. In the present study, a mouse Leydig tumor cell line (mLTC-1) was used as a model to investigate the mechanism of steroidogenic inhibition and to identify the molecular target of BPAF. Levels of progesterone and the concentration of cyclic adenosine monophosphate (cAMP) in cells exposed to BPAF were detected, and expression of key genes and proteins in steroid biosynthesis was assessed. The results showed that BPAF exposure decreased human chorionic gonadotrophin (hCG)-stimulated progesterone production in a dose-dependent manner. The 24-h IC

Tian W, Fu H, Xu T, et al.
SLC6A19 is a novel putative gene, induced by dioxins via AhR in human hepatoma HepG2 cells.
Environ Pollut. 2018; 237:508-514 [PubMed] Related Publications
The aryl hydrocarbon receptor (AhR) plays an important role in mediating dioxins toxicity. Currently, genes of P450 families are major research interests in studies on AhR-mediated gene alterations caused by dioxins. Genes related to other metabolic pathways or processes may be also responsive to dioxin exposures. Amino acid transporter B0AT1 (encoded by SLC6A19) plays a decisive role in neutral amino acid transport which is present in kidney, intestine and liver. However, effects of dioxins on its expression are still unknown. In the present study, we focused on the effects of dioxin and dioxin-like compounds on SLC6A19 expression in HepG2 cells. We identified SLC6A19 as a novel putative target gene of AhR activation in HepG2 cells. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) increased the expression of SLC6A19 in time- and concentration-dependent manners. Using AhR antagonist CH223191 and/or siRNA assays, we demonstrated that certain AhR agonists upregulated SLC6A19 expression via AhR, including TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (1,2,3,7,8-PeCDD), 2,3,4,7,8- pentachlorodibenzofuran (2,3,4,7,8-PeCDF) and PCB126. In addition, the expression of B0AT1 was also significantly induced by TCDD in HepG2 cells. Our study suggested that dioxins might affect the transcription and translation of SLC6A19 in HepG2 cells, which might be a novel putative gene to assess dioxins' toxicity in amino acid transport and metabolism in liver.

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