The PXR rs7643645 Polymorphism Is Associated with the Risk of Higher Prostate-Specific Antigen Levels in Prostate Cancer Patients

Reyes-Hernández, Octavio Daniel; Vega, Libia; Jiménez-Ríos, Miguel Ángel; Martínez-Cervera, Pedro; Lugo-García, Juan A.; Hernández‐Cadena, Leticia; Ostrosky‐Wegman, Patricia; Orozco, Lorena; Elizondo, Guillermo

doi:10.1371/journal.pone.0099974

Cited by 13 publications

(10 citation statements)

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“…These observations led to the proposition that TERE1 controls the CPRC phenotype by regulating the endogenous levels of Vitamin K-2 and hence the transcriptional control of a set of steroid catabolism genes via the PXR. Other studies corroborate PXR in a similar role in prostate cancer (Kumar et al, 2010; Reyes-Hernandez et al, 2014; Zhang et al, 2010). …”

Section: Differential Role Of Pxr In Cancersupporting

confidence: 54%

“…While some PXR polymorphisms did not seem to interact with cancer growth, progression, or drug response (Justenhoven et al, 2011; Martino et al, 2013; Tham et al, 2007), several others were found to be significantly associated with cancer risk, growth, progression, or therapeutic outcome. For instance, the PXR polymorphisms have been shown to be associated with increased lung cancer risk in smokers (Zhang et al, 2014a) (Zhang et al, 2014b), higher prostate-specific antigen levels in prostate cancer patients (Reyes-Hernandez et al, 2014), lymphoma risk (Campa et al, 2012), pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in breast cancer patients, pharmacokinetics and toxicity of irinotecan in colorectal cancer patients (Mbatchi et al, 2016), risk of colorectal cancer (Andersen et al, 2010), Barrett’s esophagus and esophageal adenocarcinoma (van de Winkel et al, 2011a), and docetaxel disposition in nasopharyngeal cancer patients (Chew et al, 2014). Hence, a complete mapping of PXR polymorphisms is required to fully understand the PXR activation in a variety of tumors.…”

Section: Future Directionsmentioning

confidence: 99%

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Pregnane X Receptor and Cancer: Context-Specificity is Key

Pondugula

Pávek

Mani

2016

Nuclear Receptor Research

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Pregnane X receptor (PXR) is an adopted orphan nuclear receptor that is activated by a wide-range of endobiotics and xenobiotics, including chemotherapy drugs. PXR plays a major role in the metabolism and clearance of xenobiotics and endobiotics in liver and intestine via induction of drug-metabolizing enzymes and drug-transporting proteins. However, PXR is expressed in several cancer tissues and the accumulating evidence strongly points to the differential role of PXR in cancer growth and progression as well as in chemotherapy outcome. In cancer cells, besides regulating the gene expression of enzymes and proteins involved in drug metabolism and transport, PXR also regulates other genes involved in proliferation, metastasis, apoptosis, anti-apoptosis, inflammation, and oxidative stress. In this review, we focus on the differential role of PXR in a variety of cancers, including prostate, breast, ovarian, endometrial, and colon. We also discuss the future directions to further understand the differential role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators to target PXR in PXR-expressing cancers.

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Section: Differential Role Of Pxr In Cancersupporting

confidence: 54%

Section: Future Directionsmentioning

confidence: 99%

Pregnane X Receptor and Cancer: Context-Specificity is Key

Pondugula

Pávek

Mani

2016

Nuclear Receptor Research

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“…A few studies have also shown that PXR has potential anti-inflammatory effects. Single-nucleotide polymorphisms linked to a decrease in PXR activity or expression level have resulted in inflammatory bowel disease in patients ( Langmann et al ., 2004 ; Dring et al ., 2006 ; Shah et al ., 2006 ; Reyes-Hernandez et al ., 2014 ; Zhang et al ., 2014 ). PXR-null mice were much easier subjected to colitis than wild-type mice ( Shah et al , 2006 ).…”

Section: Introductionmentioning

confidence: 99%

PXR Mediated Protection against Liver Inflammation by Ginkgolide A in Tetrachloromethane Treated Mice

Wang

Hong

et al. 2016

Biomolecules & Therapeutics

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The pregnane X receptor (PXR), a liver and intestine specific receptor,, has been reported to be related with the repression of inflammation as well as activation of cytochromosome P450 3A (CYP3A) expression. We examined the effect of PXR on tetrachloromethane (CCl4)-induced mouse liver inflammation in this work. Ginkgolide A, one main component of Ginkgo biloba extracts (GBE), activated PXR and enhanced PXR expression level, displayed both significant therapeutic effect and preventive effect against CCl4-induced mouse hepatitis. siRNA-mediated decrease of PXR expression significantly reduced the efficacy of Ginkgolide A in treating CCl4-induced inflammation in mice. Flavonoids, another important components of GBE, were shown anti-inflammatory effect in a different way from Ginkgolide A which might be independent on PXR because flavonoids significantly inhibited CYP3A11 activities in mice. The results indicated that anti-inflammatory effect of PXR might be mediated by enhancing transcription level of IκBα through binding of IκBα. Inhibition of NF-κB activity by NF-κB-specific suppressor IκBα is one of the potential mechanisms of Ginkgolide A against CCl4-induced liver inflammation.

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“…Genome-wide and candidate gene based association studies in prostate cancer have attempted to elucidate the role of common risk alleles affecting disease susceptibility and aggressiveness [ 12 – 14 ]. But many of these were inconclusive as a sizable fraction of disease-associated SNPs were located in non-coding region while some of them suffered from lack of replicability in other populations [ 15 – 17 ]. Non-reproducibility of genetic association studies may be explained by multiple confounding factors such as, (a) a difference in risk allele frequency between populations, (b) divergent association of an allele with risk in different populations, and (c) possible interaction of an allele with other genetic or environmental factors that vary among populations [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

A Study of Molecular Signals Deregulating Mismatch Repair Genes in Prostate Cancer Compared to Benign Prostatic Hyperplasia

et al. 2015

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Prostate cancer is one of the leading causes of mortality among aging males. There is an unmet requirement of clinically useful biomarkers for early detection of prostate cancer to reduce the liabilities of overtreatment and accompanying morbidity. The present population-based study investigates the factors disrupting expression of multiple functionally related genes of DNA mismatch repair pathway in prostate cancer patients to identify molecular attributes distinguishing adenocarcinoma from benign hyperplasia of prostate. Gene expression was compared between tissue samples from prostate cancer and benign prostatic hyperplasia using real-time-PCR, western blot and immunohistochemistry. Assessment of genotypes of seven single-nucleotide-polymorphisms of three MMR genes was conducted using PCR-coupled RFLP and sequencing. Promoter methylation was interrogated by methylation-specific-PCR and bisulfite-sequencing. Interaction between microRNAs and MMR genes was verified by 3'UTR-based dual luciferase assays. Concurrent reduction of three MMR genes namely hMLH1, hMSH6 and hMSH2 (34-85%, P<0.05) was observed in prostate cancer tissues. hMSH6 polymorphism rs1800932(Pro92Pro) conferred a borderline protection in cancer patients (OR = 0.33, 95% CI = 0.15-0.75). Relative transcript level of hMLH1 was inversely related (r = -0.59, P<0.05) with methylation quotient of its promoter which showed a significantly higher methylation density (P = 0.008, Z = -2.649) in cancer patients. hsa-miR-155, hsa-miR-141 and hsa-miR-21 gene expressions were significantly elevated (66-85%, P<0.05) in tumor specimens and negatively correlated (r = -0.602 to -0.527, P<0.05) with that of MMR genes. hsa-miR-155 & hsa-miR-141 and hsa-miR-155 & hsa-miR-21 were demonstrated to bind to their putative seed sequences in hMLH1 and hMSH6 3’UTRs respectively. Relatively higher expression of DNA methyl-transferases (DNMT1 and DNMT3b) and HIF-1α genes (34-50%, P<0.05) were also detected in tumor tissues. This study provides statistical evidence that MMR deficiency is correlated with hypermethylation of hMLH1 promoter and upregulation of hsa-miR-155, hsa-miR-141 and hsa-miR-21 in prostate cancer. This comparative study reflects that microRNA expression level, particularly hsa-miR-155, exhibits predictive signature of prostate adenocarcinoma.

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The PXR rs7643645 Polymorphism Is Associated with the Risk of Higher Prostate-Specific Antigen Levels in Prostate Cancer Patients

Cited by 13 publications

References 31 publications

Pregnane X Receptor and Cancer: Context-Specificity is Key

Pregnane X Receptor and Cancer: Context-Specificity is Key

PXR Mediated Protection against Liver Inflammation by Ginkgolide A in Tetrachloromethane Treated Mice

A Study of Molecular Signals Deregulating Mismatch Repair Genes in Prostate Cancer Compared to Benign Prostatic Hyperplasia

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