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A Microuidics-Driven Cloud Service: Genomic Association Studies
Published in Mohamed Ibrahim, Krishnendu Chakrabarty, Optimization of Trustworthy Biomolecular Quantitative Analysis Using Cyber-Physical Microfluidic Platforms, 2020
Mohamed Ibrahim, Krishnendu Chakrabarty
Figure 4.3 shows the multi-omic analysis flow for breast cancer investigation [211]—we apply this flow to both cancer and normal cells for comparison. First, genotyping of tumor samples is performed to select gene probes and to determine the associated SNPs per each gene probe within a pre-specified window size (e.g., 1 MB window). Next, regression techniques are applied to assess the association between each expression probe and the SNPs in single and multivariate models (e.g., SNP-CpG [199]). The SNPs of probes with increasing expression activity, such as CYP1B1 gene, may result in high risks of carcinogenic instances. Likewise, genetic rare variants (or SNPs) in COMT gene can reduce the metabolism of carcinogenic product, resulting in a higher level of DNA damage. Even so, these variations may not increase the risk of cancer if the DNA-damage repair can adequately absorb carcinogenic metabolites. In other words, using variations in genetic and transcriptomic association solely as a signature for breast cancer could be misleading.
Cytochrome P450 1B1 promotes cancer cell survival via specificity protein 1 (Sp1)-mediated suppression of death receptor 4
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Yeo-Jung Kwon, Nam-Hyeon Cho, Dong-Jin Ye, Hyoung-Seok Baek, Yeon-Sang Ryu, Young-Jin Chun
To identify the role of CYP1B1 in cancer cell survival, cell viability assay was conducted with specific CYP1B1 inhibitor in human breast cancer and leukemia cell lines. The selective inhibition of CYP1B1 by TMS was first reported by Chun et al. (2001), using TMS, and Chun et al. (2009) noted a similar specific inhibitory effect of TMS on oncogenic action. TMS was utilized in this investigation. As shown in Figure 1, cell viability of breast cancer cell lines, MCF-7 and MDA-MB-231, and leukemia cell lines, HL-60 and U937, was significantly reduced by TMS in a concentration-dependent manner. In addition, TMS also suppressed CYP1B1 protein expression in these cell lines. Data thus suggest that CYP1B1 may play an important role in cancer cell proliferation.
Regulation of cytochrome P450 expression by microRNAs and long noncoding RNAs: Epigenetic mechanisms in environmental toxicology and carcinogenesis
Published in Journal of Environmental Science and Health, Part C, 2019
Dongying Li, William H. Tolleson, Dianke Yu, Si Chen, Lei Guo, Wenming Xiao, Weida Tong, Baitang Ning
The pioneering work of Tsuchiya et al.92 first identified and validated miR-27b as a post-transcriptional repressor of CYP1B1. CYP1B1 is responsible for the bioactivation of many procarcinogens and CYP1B1 overexpression and increased enzyme activity have been observed in lung, colon, and breast cancers.118 Stable hybridization between miR-27b and its MRE located in the 3′-UTR of the CYP1B1 mRNA transcript was demonstrated using RNase protection assays and the function of this regulatory mechanism was confirmed using luciferase reporter assays upon miR-27b overexpression or introduction of miR-27b inhibitors; the level of miR-27b was inversely correlated with luciferase activity with reporter gene constructs including the CYP1B1 miR-27-MRE. Gain- and loss-of-function assays have also demonstrated that miR-27b binds to CYP1B1 mRNA and decreases CYP1B1 expression and enzymatic activity.92 miRNAs can also affect CYP expression indirectly by targeting transcriptional activators or repressors of CYP expression (Table 3). For instance, the CYP3A4 gene is regulated by multiple NRs, including PXR, farnesoid X receptor (FXR), and CAR.131,132 Takagi et al.123 have shown that CYP3A4 expression is inhibited at both the mRNA and protein levels upon PXR repression by miR-148. Additionally, miR-34a, miR-30c-1-3p, and miR-27b downregulate CYP3A4 by targeting retinoid X receptor α (RXRα), PXR, and VDR, respectively.108,121,122 When a transcriptional repressor of CYPs is targeted by a miRNA, miRNA-dependent silencing of the repressor will lead to an increase of the CYP level. For example, in CYP2D6-humanized mice, feeding cholic acid leads to a significant decrease of small heterodimer partner (SHP) at the protein level by upregulating miR-142-3p, which targets SHP; miR-142-3p-mediated SHP reduction is accompanied by an increase of CYP2D6 mRNA and protein expression, indicating a potential role of bile acid levels in the transcriptional control of CYP2D6.119Table 3 presents published reports of indirect regulatory pathways by which miRNAs affect the expression of trans-regulatory factors that then regulate CYP genes. It should be noted that additional complexity results from the fact that additional CYP genes are regulated by HNF1A, HNF4A, VDR, and PXR.133,134 Similar miRNA-dependent regulatory pathways involving these CYP genes will require further investigation. Other transcription factors shown to influence the expression of CYP genes, such as the glucocorticoid receptor and FXR, provide additional regulatory targets for miRNA species that could be explored.135,136 miRNAs regulate CYP expression at multiple levels through diverse and novel mechanisms. In the case of CYP2E1, a miRNA species affects transcription by interfering with the assembly of transcription machinery on the promotor region. The multiple mechanisms by which the expression of CYP2E1 is influenced by different miRNAs provides illuminating examples of diverse regulatory systems.