Cyclooxygenase‐2 gene promoter polymorphisms affect susceptibility to hepatitis C virus infection and disease progression

Sakaki, Masashi; Makino, Reiko; Hiroishi, Kazumasa; Eguchi, Junichi; Hiraide, Ayako; Doi, Hiroyoshi; Omori, Risa; Imawari, Michio

doi:10.1111/j.1872-034x.2010.00727.x

Cited by 21 publications

(23 citation statements)

References 36 publications

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“…In fact, in a recently published study we reported that this polymorphism located at −1195 nucleotides upstream exon 1 increases COX-2 transcriptional activity in two colon cancer cell lines [30]. This was also noticeable in human hepatoma cell lines [31] but antagonizes the increased promoter activity observed for the rs689466 A allele in gastric cancer cell lines [25]. COX-2 overexpression is suggested as one of the smoke-induced pathways involved in carcinogenesis [32], [33].…”

Section: Discussionmentioning

confidence: 75%

Genetic Variability in Key Genes in Prostaglandin E2 Pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and Their Involvement in Colorectal Cancer Development

et al. 2014

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The pro-carcinogenic effects of prostaglandin E2 (PGE2) in colonic mucosa are not only regulated by the rates between Cyclooxygenase-2 (COX-2) biosynthesis and 15-Hydroxyprostaglandin Dehydrogenase (15-PGDH)-dependent degradation but also the steady-state levels of PGE2 in extracellular microenvironment, maintained by key specific prostaglandin transporters, the Multidrug Resistance Protein (MRP4) (efflux carrier) and Prostaglandin Transporter (PGT) (influx carrier). To understand the contribution of genetic variability in genes coding for COX-2/15-PGDH/MRP4/PGT proteins in CRC development, we conducted a hospital-based case-control study involving 246 CRC patients and 480 cancer-free controls. A total of 51 tagSNPs were characterized using the Sequenom platform through multiplexed amplification followed by mass-spectrometric product separation or allelic discrimination using real-time PCR. Seven tagSNPs were implicated in CRC development: the rs689466 in COX-2 gene, the rs1346271 and rs1426945 in 15-PGDH, the rs6439448 and rs7616492 in PGT and rs1751051 and rs1751031 in MRP4 coding genes. Upon a stratified analysis a measurable gene-environment interaction was noticed between rs689466 and smoking habits, with individuals ever-smokers carriers of rs689466 GG homozygous genotype having a nearly 6-fold increased susceptibility for CRC onset (95%CI: 1.49–22.42, P = 0.011). Furthermore, the multifactor dimensionality reduction (MDR) analysis identified an overall four-factor best gene-gene interactive model, including the rs1426945, rs6439448, rs1751051 and rs1751031 polymorphisms. This model had the highest cross-validation consistency (10/10, P<0.0001) and an accuracy of 0.6957 and was further associated with a 5-fold increased risk for CRC development (95%CI: 3.89–7.02, P<0.0001). In conclusion, specific low penetrance genes in the pro-carcinogenic PGE2 pathway appear to modulate the genetic susceptibility for CRC development. A clearer understanding on CRC etiology through the identification of biomarkers of colorectal carcinogenesis might allow a better definition of risk models that are more likely to benefit from targeted preventive strategies to reduce CRC burden.

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Section: Discussionmentioning

confidence: 75%

Genetic Variability in Key Genes in Prostaglandin E2 Pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and Their Involvement in Colorectal Cancer Development

et al. 2014

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“…A previous study indicated that the microsatellite polymorphisms of the promoter/enhancer region of FOXP3 were not associated with chronic HCV infection [24], and in our study, we did not receive hepatitis C patients or hepatitis C-related HCC patients, preventing our discussion of FOXP3 gene polymorphisms in HCV infection. Current studies have rarely reported concrete relevance for FOXP3 expression in tumors; the transcript types and biological significance of FOXP3 in cancer remains unclear.…”

Section: Discussionmentioning

confidence: 91%

FOXP3 gene polymorphism is associated with hepatitis B-related hepatocellular carcinoma in China

Chen

Zhang

Liao

et al. 2013

J Exp Clin Cancer Res

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BackgroundPrevious evidence has shown that the FOXP3 gene was involved in the pathogenesis of several tumors; however, the correlation between single nucleotide polymorphisms (SNPs) in the FOXP3 gene and the susceptibility to hepatitis B-related hepatocellular carcinoma (HCC) remains unclear.MethodsWe analyzed two SNPs in the FOXP3 gene, rs2280883 and rs3761549, in 392 patients with HCC, 344 patients with chronic hepatitis B (CHB) and 372 matched healthy controls. Genotyping was performed by MALDI-TOF Mass Spectrometry for all donors.ResultsCompared to healthy controls, HCC patients had higher frequencies of the TT genotype (79.6%) at rs2280883 and the CC genotype (77.6%) at rs3761549 of the FOXP3 gene; CHB patients also had higher frequencies of the TT genotype (74.1%) at rs2280883 and the CC genotype (74.6%) at rs3761549. There were no significant differences in the distribution of FOXP3 genotypes between CHB donors and HCC donors. The TT genotype at rs2280883 was more frequent in patients with HCC than healthy donors (P = 0.01), but no significant difference was observed in this genotype between CHB and healthy donors (P = 0.479). C allele frequency at rs3761549 was higher in HCC patients than healthy donors (P = 0.03), but distribution of this allele was not significantly different between CHB patients and healthy donors (P = 0.11). Stratified analysis showed that the CC genotype at rs3761549 was significantly associated with a high incidence of portal vein tumor thrombus (P = 0.02) and that the TT/CT genotype at rs3761549 was significantly associated with an increased rate of tumor recurrence in HCC patients (P = 0.001).ConclusionsOur results suggested that the FOXP3 gene polymorphisms at rs2280883 and rs3761549 may be associated with hepatitis B-related HCC. At rs3761549, the CC genotype and the TT/CT genotype were associated with a high incidence of portal vein tumor thrombus and tumor recurrence, respectively.

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“…Multiple studies have illustrated that HCV proteins dramatically stimulate COX-2 expression, which is associated with carcinogenesis [9], [32]. To investigate whether the EC isomers could suppress HCV-induced COX-2 expression, we measured the transcription and translation levels of COX-2 in EC-treated Ava5 cells.…”

Section: Resultsmentioning

confidence: 99%

Green Tea Phenolic Epicatechins Inhibit Hepatitis C Virus Replication via Cycloxygenase-2 and Attenuate Virus-Induced Inflammation

Lin

Tseng

et al. 2013

PLoS ONE

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Chronic hepatitis C virus (HCV) infection is the leading risk factor for hepatocellular carcinoma (HCC) and chronic liver disease worldwide. Green tea, in addition to being consumed as a healthy beverage, contains phenolic catechins that have been used as medicinal substances. In the present study, we illustrated that the epicatechin isomers (+)-epicatechin and (−)-epicatechin concentration-dependently inhibited HCV replication at nontoxic concentrations by using in vitro cell-based HCV replicon and JFH-1 infectious systems. In addition to significantly suppressing virus-induced cyclooxygenase-2 (COX-2) expression, our results revealed that the anti-HCV activity of the epicatechin isomers occurred through the down-regulation of COX-2. Furthermore, both the epicatechin isomers additively inhibited HCV replication in combination with either interferon-α or viral enzyme inhibitors [2′-C-methylcytidine (NM-107) or telaprevir]. They also had prominent anti-inflammatory effects by inhibiting the gene expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and inducible nitrite oxide synthase as well as the COX-2 in viral protein-expressing hepatoma Huh-7 cells. Collectively, (+)-epicatechin and (−)-epicatechin may serve as therapeutic supplements for treating HCV-related diseases.

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Cyclooxygenase‐2 gene promoter polymorphisms affect susceptibility to hepatitis C virus infection and disease progression

Cited by 21 publications

References 36 publications

Genetic Variability in Key Genes in Prostaglandin E2 Pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and Their Involvement in Colorectal Cancer Development

Genetic Variability in Key Genes in Prostaglandin E2 Pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and Their Involvement in Colorectal Cancer Development

FOXP3 gene polymorphism is associated with hepatitis B-related hepatocellular carcinoma in China

Green Tea Phenolic Epicatechins Inhibit Hepatitis C Virus Replication via Cycloxygenase-2 and Attenuate Virus-Induced Inflammation

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