PON1

Gene Summary

Gene:PON1; paraoxonase 1
Aliases: ESA, PON, MVCD5
Location:7q21.3
Summary:The enzyme encoded by this gene is an arylesterase that mainly hydrolyzes paroxon to produce p-nitrophenol. Paroxon is an organophosphorus anticholinesterase compound that is produced in vivo by oxidation of the insecticide parathion. Polymorphisms in this gene are a risk factor in coronary artery disease. The gene is found in a cluster of three related paraoxonase genes at 7q21.3. [provided by RefSeq, Oct 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:serum paraoxonase/arylesterase 1
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
Show (19)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 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.

  • Gene Expression
  • Polymerase Chain Reaction
  • Staging
  • Aryldialkylphosphatase
  • Haplotypes
  • Environmental Exposure
  • SEER Program
  • Restriction Fragment Length Polymorphism
  • Brain Tumours
  • Oxidative Stress
  • Pesticides
  • Lung Cancer
  • Reactive Oxygen Species
  • Brain Tumours
  • Asian Continental Ancestry Group
  • Polycystic Ovary Syndrome
  • Alleles
  • Tandem Mass Spectrometry
  • Single Nucleotide Polymorphism
  • Odds Ratio
  • Logistic Models
  • Promoter Regions
  • Childhood Cancer
  • Genetic Predisposition
  • Adolescents
  • Smoking
  • Genotype
  • Polymorphism
  • Cytochrome P-450 Enzyme System
  • STAT6 Transcription Factor
  • DNA Damage
  • Risk Assessment
  • Carboxylic Ester Hydrolases
  • Genetic Association Studies
  • Surveys and Questionnaires
  • Prostate Cancer
  • Breast Cancer
  • Case-Control Studies
  • Glutathione Transferase
  • Chromosome 7
  • Risk Factors
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: PON1 (cancer-related)

Gu HF, Mou M, Liang ZG, et al.
The association between paraoxonase 1 gene polymorphisms and polycystic ovarian syndrome.
Cell Mol Biol (Noisy-le-grand). 2016; 62(14):44-47 [PubMed] Related Publications
Some studies investigated the association of paraoxonase 1 (PON1) polymorphisms with polycystic ovarian syndrome (PCOS) risk. However, the result was still inconsistent. The aim of this study was to investigate whether there is an association between the PON1 polymorphisms and PCOS risk. Electronic databases, such as PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) databases, were searched for identification of the studies. The associations between PON1 polymorphisms and PCOS risk was quantified using ORs with 95% CIs. A total of 8 eligible studies with 2272 cases and 1811 controls were included in this meta-analysis. PON1 Leu55Met polymorphism was associated with a significantly increased risk of PCOS (OR=1.31; 95%CI, 1.10-1.55). However, no association was found in Asians and Caucasians (Table 2). We also found that PON1 Q192R polymorphism was associated with a significantly increased risk of PCOS (OR=1.81; 95%CI, 1.17-2.82). Additionally, this polymorphism increased PCOS risk in Asians (OR=1.26; 95%CI, 1.13-1.41). Furthermore, PON1 C108T polymorphism showed increased PCOS risk (OR=1.46; 95%CI, 1.08-1.97). No association between this polymorphism and PCOS risk was found in Asians and Caucasians. In conclusion, this meta-analysis suggested that PON1 polymorphisms were associated with PCOS risk.

GallegosVargas J, SanchezRoldan J, RonquilloSanchez M, et al.
Gene Expression of CYP1A1 and its Possible Clinical Application in Thyroid Cancer Cases.
Asian Pac J Cancer Prev. 2016; 17(7):3477-82 [PubMed] Related Publications
BACKGROUND: Thyroid cancer is the most common endocrine malignancy, and exact causes remain unknown. The role of CYP450 1A1 (CYP1A1) in cancer initiation and progression has been investigated. The aim of this work was to analyze, for the first time, CYP1A1 gene expression and its relationship with several clinicopathological factors in Mexican patients diagnosed with thyroid cancer.
MATERIALS AND METHODS: Realtime PCR analysis was conducted on 32 sets of thyroid tumors and benign pathologies. Expression levels were tested for correlations with clinical and pathological data. All statistical analysis were performed using GraphPad Prism version 3.0 software.
RESULTS: We found that female gender was associated with thyroid cancer risk (P<0.05). A positive relationship was identified between CYP1A1 mRNA levels and the presence of chronic disease, alcohol use, tumor size, metastasis and an advanced clinical stage (P<0.05).
CONCLUSIONS: The results suggest that CYP1A1 gene expression could be used as a marker for thyroid cancer.

Cheung SK, Chuang PK, Huang HW, et al.
Stage-specific embryonic antigen-3 (SSEA-3) and β3GalT5 are cancer specific and significant markers for breast cancer stem cells.
Proc Natl Acad Sci U S A. 2016; 113(4):960-5 [PubMed] Free Access to Full Article Related Publications
The discovery of cancer stem cells (CSCs), which are responsible for self-renewal and tumor growth in heterogeneous cancer tissues, has stimulated interests in developing new cancer therapies and early diagnosis. However, the markers currently used for isolation of CSCs are often not selective enough to enrich CSCs for the study of this special cell population. Here we show that the breast CSCs isolated with CD44(+)CD24(-/lo)SSEA-3(+) or ESA(hi)PROCR(hi)SSEA-3(+) markers had higher tumorigenicity than those with conventional markers in vitro and in vivo. As few as 10 cells with CD44(+)CD24(-/lo)SSEA-3(+) formed tumor in mice, compared with more than 100 cells with CD44(+)CD24(-/lo). Suppression of SSEA-3 expression by knockdown of the gene encoding β-1,3-galactosyltransferase 5 (β3GalT5) in the globo-series pathway, led to apoptosis in cancer cells specifically but had no effect on normal cells. This finding is further supported by the analysis of SSEA-3 and the two related globo-series epitopes SSEA4 and globo-H in stem cells (embryonic stem cells and induced pluripotent stem cells) and various normal and cancer cells, and by the antibody approach to target the globo-series glycans and the late-stage clinical trials of a breast cancer vaccine.

Lao X, Wang X, Liu Y, et al.
Association of Paraoxonase 1 Gene Polymorphisms With the Risk of Hepatitis B Virus-related Liver Diseases in a Guangxi Population: A Case-control Study.
Medicine (Baltimore). 2015; 94(48):e2179 [PubMed] Free Access to Full Article Related Publications
Paraoxonase 1 (PON1), a liver-induced glycoprotein enzyme responsible for antioxidant defense against reactive oxygen species and anti-inflammatory, has been linked to various cancers. The objective of this study was to explore the association of PON1 rs662 and rs705382 with the risk of chronic hepatitis B (CHB), hepatitis B virus-related liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in patients living in the Guangxi region of southern China. The PON1 rs662 and rs705382 single-nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 99 CHB patients, 84 LC patients, 258 HCC patients, and 221 healthy controls.Significant associations with CHB risk were observed for the rs705382 SNP after adjusting for sex, age, ethnicity, smoking, alcohol consumption, and body mass index. When stratified by sex and age, this positive association was significantly strengthened among men and individuals over 40 years old. Moreover, a decreased risk of LC was associated with the rs705382 CG and the combined GG + CG genotypes among women, with borderline statistical significance. In haplotype analyses, the haplotype GA was associated with a 1.68-fold increase in the risk of HCC.Our results showed that the PON1 rs705382 SNP might be a risk factor for CHB in Guangxi populations.

Pon JR, Marra MA
MEF2 transcription factors: developmental regulators and emerging cancer genes.
Oncotarget. 2016; 7(3):2297-312 [PubMed] Free Access to Full Article Related Publications
The MEF2 transcription factors have roles in muscle, cardiac, skeletal, vascular, neural, blood and immune system cell development through their effects on cell differentiation, proliferation, apoptosis, migration, shape and metabolism. Altered MEF2 activity plays a role in human diseases and has recently been implicated in the development of several cancer types. In particular, MEF2B, the most divergent and least studied protein of the MEF2 family, has a role unique from its paralogs in non-Hodgkin lymphomas. The use of genome-scale technologies has enabled comprehensive MEF2 target gene sets to be identified, contributing to our understanding of MEF2 proteins as nodes in complex regulatory networks. This review surveys the molecular interactions of MEF2 proteins and their effects on cellular and organismal phenotypes. We include a discussion of the emerging roles of MEF2 proteins as oncogenes and tumor suppressors of cancer. Throughout this article we highlight similarities and differences between the MEF2 family proteins, including a focus on functions of MEF2B.

Liu T, Hu K, Zhao Z, et al.
MicroRNA-1 down-regulates proliferation and migration of breast cancer stem cells by inhibiting the Wnt/β-catenin pathway.
Oncotarget. 2015; 6(39):41638-49 [PubMed] Free Access to Full Article Related Publications
We investigated the miRNA profiles of breast cancer stem cells (CSCs) and non-CSC tumor cells by miRNA microarray and determined the effect of altered miR-1 expression on proliferation and migration of breast CSCs. The potential targets of miR-1 in the Wnt/β-catenin signaling were characterized by bioinformatics analysis and luciferase assay. We found that 14 miRNAs were up-regulated and 13 were down-regulated in the ESA+CD44+CD24-lineage- CSCs, related to ESA+CD44-CD24+lineage- non-CSC tumor cells. The miR-1 expression was associated inversely with aggressiveness of breast cancers. Furthermore, enhanced miR-1 expression decreased the percentages of SKBR3/CSCs and miR-1 inhibition increased the percentages of MCF-7/CSCs. Enhanced miR-1 expression significantly reduced the Frizzled 7 and Tankyrase-2 (TNKS2)-regulated luciferase activity in 293T cells and decreased Frizzled 7, TNKS2, c-Myc, octamer-binding transcription factor 4 (Oct4) and Nanog expression and the ratios of nuclear to cytoplasmic β-catenin as well as β-catenin-dependent luciferase activity in breast CSCs in vitro. miR-1 inhibited proliferation, migration and wound healing of breast CSCs in vitro. Enhanced miR-1 expression inhibited the growth of implanted MCF-7/CSCs while miR-1 inhibition promoted the growth of implanted MCF-7/CSCs in vivo. Our data indicate that miR-1 down-regulates breast CSC stemness, proliferation and migration by targeting the Frizzled 7 and TNKS2 to inhibit the Wnt/β-catenin signaling.

Pon JR, Marra MA
Clinical impact of molecular features in diffuse large B-cell lymphoma and follicular lymphoma.
Blood. 2016; 127(2):181-6 [PubMed] Related Publications
Our understanding of the pathogenesis and heterogeneity of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) has been dramatically enhanced by recent attempts to profile molecular features of these lymphomas. In this article, we discuss ways in which testing for molecular features may impact DLBCL and FL management if clinical trials are designed to incorporate such tests. Specifically, we discuss how distinguishing lymphomas on the basis of cell-of-origin subtypes or the presence of other molecular features is prognostically and therapeutically significant. Conversely, we discuss how the molecular similarities of DLBCL and FL have provided insight into the potential of both DLBCL and FL cases to respond to agents targeting alterations they have in common. Through these examples, we demonstrate how the translation of our understanding of cancer biology into improvements in patient outcomes depends on analyzing the molecular correlates of treatment outcomes in clinical trials and in routinely treated patients.

Feng ZM, Qiu J, Chen XW, et al.
Essential role of miR-200c in regulating self-renewal of breast cancer stem cells and their counterparts of mammary epithelium.
BMC Cancer. 2015; 15:645 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer stem cells (BCSCs) have been reported as the origin of breast cancer and the radical cause of drug resistance, relapse and metastasis in breast cancer. BCSCs could be derived from mutated mammary epithelial stem cells (MaSCs). Therefore, comparing the molecular differences between BCSCs and MaSCs may clarify the mechanism underlying breast carcinogenesis and the targets for gene therapy. Specifically, the distinct miRNome data of BCSCs and MaSCs need to be analyzed to find out the key miRNAs and reveal their roles in regulating the stemness of BCSCs.
METHODS: MUC1(-)ESA(+) cells were isolated from normal mammary epithelial cell line MCF-10A by fluorescence-activated cell sorting (FACS) and tested for stemness by clonogenic assay and multi-potential differentiation experiments. The miRNA profiles of MaSCs, BCSCs and breast cancer MCF-7 cells were compared to obtain the candidate miRNAs that may regulate breast tumorigenesis. An miRNA consecutively upregulated from MaSCs to BCSCs to MCF-7 cells, miR-200c, was chosen to determine its role in regulating the stemness of BCSCs and MaSCs in vitro and in vivo. Based on bioinformatics, the targets of miR-200c were validated by dual-luciferase report system, western blot and rescue experiments.
RESULTS: In a 2-D clonogenic assay, MUC1(-)ESA(+) cells gave rise to multiple morphological colonies, including luminal colonies, myoepithelial colonies and mixed colonies. The clonogenic potential of MUC1(-)ESA(+) (61.5 ± 3.87 %) was significantly higher than that of non-stem MCF-10A cells (53.5 ± 3.42 %) (P < 0.05). In a 3-D matrigel culture, MUC1(-)ESA(+) cells grew into mammospheres with duct-like structures. A total of 12 miRNAs of interest were identified, 8 of which were upregulated and 4 downregulated in BCSCs compared with MaSCs. In gain- and lost-of-function assays, miR-200c was sufficient to inhibit the self-renewal of BCSCs and MaSCs in vitro and the growth of BCSCs in vivo. Furthermore, miR-200c negatively regulated programmed cell death 10 (PDCD10) in BCSCs and MaSCs. PDCD10 could rescue the tumorigenesis inhibited by miR-200c in BCSCs.
DISCUSSION: Accumulating evidence shows that there is a milignant transformation from MaSCs into BCSCs. The underlying mechanism remains unclear. In present study, miRNA profiles between MaSCs and BCSCs were obtained. Then miRNA-200c, downregulated in both MaSCs and BCSCs, were verified as anti-oncogene, and played essential role in regulating self-renewal of both kinds of stem-like cells. These findings reveal a novel insights of breast tumorigenesis.
CONCLUSIONS: PDCD10 is a target gene of miR-200c and also a possible mechanism by which miR-200c plays a role in regulating the stemness of BCSCs and MaSCs.

Sai S, Vares G, Kim EH, et al.
Carbon ion beam combined with cisplatin effectively disrupts triple negative breast cancer stem-like cells in vitro.
Mol Cancer. 2015; 14:166 [PubMed] Free Access to Full Article Related Publications
AIMS: Although a relatively small proportion of all breast cancer (BC), triple negative (TN) BC is responsible for a relatively large proportion of BC deaths because of its worse clinical outcome. To investigate whether a carbon ion beam alone or in combination with cisplatin (CDDP) has a beneficial effect compared to X-rays, we target triple negative (TN) breast cancer stem-like cells (CSCs).
METHODS: Human breast CSCs sorted from MDA-MB-231 and MDA-MB-453 cells were treated with a carbon ion beam or X-ray irradiation alone or in combination with CDDP, and then colony, spheroid and tumor formation assays, RT-PCR Array analysis, and immunofluorescence γH2AX foci assay were performed.
RESULTS: The colony, spheroid formation, and tumorigenicity assays confirmed that CD44+/CD24- and ESA+/CD24- cells have CSC properties in MDA-MB-231 and MDA-MB-453 cells, respectively. The proportion of CSCs was more enriched after CDDP combination with either X-ray or carbon ion beam, however carbon ion beam combined with CDDP significantly suppressed colony and spheroid formation and more significantly inhibited cell cycle progression (sub-G1 arrest) compared to X-ray combined with CDDP or carbon ion beam alone. RT-PCR Array analysis showed that carbon ion beam combined with CDDP significantly induced apoptosis-related Cytochrome c, almost completely eliminated expression of the CSC markers CD44 and ESA, and significantly inhibited angiogenesis, and metastasis-related HIF1α and CD26 compared to carbon ion beam alone, X-ray alone, or X-ray combined with CDDP. The immunofluorescence assay showed that not only the number but also the size of γH2AX foci in CSCs were larger 24 h after carbon ion beam combined with CDDP compared to those of X-ray alone and X-ray combined with CDDP.
CONCLUSIONS: Carbon ion beam combined with CDDP has superior potential to kill TN breast CSCs with irreparable severe DNA damage and enhanced apoptosis.

Niroula A, Vihinen M
Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2.
Hum Mutat. 2015; 36(12):1128-34 [PubMed] Related Publications
Variations in mismatch repair (MMR) system genes are causative of Lynch syndrome and other cancers. Thousands of variants have been identified in MMR genes, but the clinical relevance is known for only a small proportion. Recently, the InSiGHT group classified 2,360 MMR variants into five classes. One-third of variants, majority of which is nonsynonymous variants, remain to be of uncertain clinical relevance. Computational tools can be used to prioritize variants for disease relevance investigations. Previously, we classified 248 MMR variants as likely pathogenic and likely benign using PON-MMR. We have developed a novel tool, PON-MMR2, which is trained on a larger and more reliable dataset. In performance comparison, PON-MMR2 outperforms both generic tolerance prediction methods as well as methods optimized for MMR variants. It achieves accuracy and MCC of 0.89 and 0.78, respectively, in cross-validation and 0.86 and 0.69, respectively, on an independent test dataset. We classified 354 class 3 variants in InSiGHT database as well as all possible amino acid substitutions in four MMR proteins. Likely harmful variants mainly appear in the protein core, whereas likely benign variants are on the surface. PON-MMR2 is a highly reliable tool to prioritize variants for functional analysis. It is freely available at http://structure.bmc.lu.se/PON-MMR2/.

Ma C, Huang T, Ding YC, et al.
MicroRNA-200c overexpression inhibits chemoresistance, invasion and colony formation of human pancreatic cancer stem cells.
Int J Clin Exp Pathol. 2015; 8(6):6533-9 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Cancer stem cells (CSCs) are believed to be 'seed cell' in cancer recurrence and metastasis. MicroRNAs (miRNAs) have emerged as potential therapeutic candidates due to their ability to regulate multiple targets involved in tumor progression and chemoresistance. The goal of this study was to investigate the role of miRNA-200c (miR-200c) in regulating colony formation, invasion and chemoresistance of human pancreatic cancer stem cells (PCSCs).
METHODS: PCSCs with CD24(+)CD44(+)ESA(+) as the marker was sorted from PANC-1 cell line by fluorescence activated cell sorter (FACS). Quantitative real-time PCR (qRT-PCR) assay was used to detect the expression of miR-200c in PCSCs and PANC-1 cells. Transfection of miR-200c mimic into PCSCs was performed to establish miR-200c over-expressed cells. The effects of overexpressing miR-200c on PCSCs were examined by cell colony forming, invasion and survival assays in vitro.
RESULTS: Our data showed that CD24(+)CD44(+)ESA(+) PCSCs (0.5%) were isolated from PANC-1 cells. Expression of miR-200c was significantly reduced in PCSCs compared with PANC-1 cells. In addition, the capability of colony formation, invasion and chemoresistance were markedly increased in PCSCs than that in PANC-1 cells. Adverse results were obtained in miR-200c overexpressing PCSCs transfected with miR-200c mimic.
CONCLUSION: Our study demonstrated that miR-200c overexpression could decrease colony formation, invasion and chemoresistance of PCSCs. It may become a new therapeutic target for gene therapy in patients suffered from pancreatic cancer.

Tomatir AG, Pehlivan S, Sahin HH, et al.
Q192R and L55M Polymorphisms of Paraoxonase 1 Gene in Chronic Myelogenous Leukemia and Chronic Lymphocytic Leukemia.
Anticancer Res. 2015; 35(9):4807-12 [PubMed] Related Publications
AIM: The aim of the present study was to investigate the association between Paraoxonase 1 (PON1) gene polymorphisms Q192R, and L55M in patients with Chronic Myelogenous Leukemia (CML) and Chronic Lymphocytic Leukemia (CLL) patients.
MATERIALS AND METHODS: We analyzed samples from 60 patients with CML, 60 with CLL and 84 healthy controls. Polymerase Chain Reaction (PCR)--Restriction Fragment Length Polymorphism (RLFP) was performed and samples were run in agarose gel.
RESULTS: We found statistically significant results showing an increase in both the RR genotype (p=0.044) and the R allele (p=0.011) for PON1 Q192R, and an increase in the MM genotype (p=0.007) and a decrease in the LL genotype (p=0.004) and R allele (p=0.001) in PON1 L55M in patients with CLL.
CONCLUSION: We concluded that both the Q192R gene polymorphism with an increase in the genotype R allele, and the M/L55 with an increase in the MM genotype play a role in CLL susceptibility, and a decrease in the LL genotype can act against disease in the Turkish population.

Pon JR, Wong J, Saberi S, et al.
MEF2B mutations in non-Hodgkin lymphoma dysregulate cell migration by decreasing MEF2B target gene activation.
Nat Commun. 2015; 6:7953 [PubMed] Free Access to Full Article Related Publications
Myocyte enhancer factor 2B (MEF2B) is a transcription factor with mutation hotspots at K4, Y69 and D83 in diffuse large B-cell lymphoma (DLBCL). To provide insight into the regulatory network of MEF2B, in this study, we analyse global gene expression and DNA-binding patterns. We find that candidate MEF2B direct target genes include RHOB, RHOD, CDH13, ITGA5 and CAV1, and that indirect target genes of MEF2B include MYC, TGFB1, CARD11, MEF2C, NDRG1 and FN1. MEF2B overexpression increases HEK293A cell migration and epithelial-mesenchymal transition, and decreases DLBCL cell chemotaxis. K4E, Y69H and D83V MEF2B mutations decrease the capacity of MEF2B to activate transcription and decrease its' effects on cell migration. The K4E and D83V mutations decrease MEF2B DNA binding. In conclusion, our map of the MEF2B regulome connects MEF2B to drivers of oncogenesis.

González-Herrera L, Gamas-Trujillo PA, Medina-Escobedo G, et al.
The Paraoxonase 1 Gene c.-108C>T SNP in the Promoter Is Associated with Risk for Glioma in Mexican Patients, but Not the p.L55M or p.Q192R Polymorphisms in the Coding Region.
Genet Test Mol Biomarkers. 2015; 19(9):494-9 [PubMed] Related Publications
AIM: To evaluate the association of the paraoxonase 1 (PON1) gene polymorphisms c.-108C>T, p.L55M, and p.Q192R with the risk of glioma in Southeast Mexico. Decreased PON1 activity caused by polymorphisms has been observed in gliomas, thus supporting the theory that PON1 is involved in tumorigenesis in the brain.
METHODS: Sixty-seven glioma patients and 58 control individuals were included. Three PON1 polymorphisms were genotyped by real-time PCR allelic discrimination using TaqMan probes: c.-108C>T in the promoter region, p.Q192R and p.L55M, both of which were in the coding region. Allele, genotype, and haplotype frequencies were assessed in cases and controls to test for statistical associations (STATA 10.2 package).
RESULTS: Significant differences were found for the PON1 c.-108C>T polymorphism between the cases and controls. Compared to the controls the cases were more likely to be CT heterozygous (p =  0.002) or TT homozygous (p = 0.036); similarly cases were more likely to possess a T allele (p = 0.032). In contrast, the p.L55M and p.Q192R polymorphisms did not show significant differences between the glioma cases and controls (p > 0.05).
CONCLUSION: The PON1 c.-108C>T polymorphism in the promoter region is associated with genetic risk for glioma. Conversely, p.L55M and p.Q192R polymorphisms in the coding region do not seem to have an influence in this population.

Rinaldi C, Bramanti P, Famà A, et al.
GLYOXALASE I A111E, PARAOXONASE 1 Q192R AND L55M POLYMORPHISMS IN ITALIAN PATIENTS WITH SPORADIC CEREBRAL CAVERNOUS MALFORMATIONS: A PILOT STUDY.
J Biol Regul Homeost Agents. 2015 Apr-Jun; 29(2):493-500 [PubMed] Related Publications
It is already known that the conditions of increased oxidative stress are associated to a greater susceptibility to vascular malformations including cerebral cavernous malformations (CCMs). These are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1(Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Polymorphisms in the genes encoding for enzymes involved in the antioxidant systems such as glyoxalase I (GLO I) and paraoxonase I (PON I) could influence individual susceptibility to the vascular malformations. A single nucleotide polymorphism was identified in the exon 4 of GLO 1 gene that causes an amino acid substitution of Ala for Glu (Ala111Glu). Two common polymorphisms have been described in the coding region of PON1, which lead to glutamine → arginine substitution at 192 (Q192R) and a leucine → methionine substitution at 55 (L55M). The polymorphisms were characterized in 59 patients without mutations in the CCM genes versus 213 healthy controls by PCR/RFLP methods using DNA from lymphocytes. We found that the frequency of patients carrying the GLO1 A/E genotype among the case group (56%) was four-fold higher than among the controls (14.1%). In the cohort of CCM patients, an increase in the frequency of PON192 Q/R genotype was observed (39% in the CCM group versus 3.7% in the healthy controls). Similarly, an increase was observed in the proportion of individuals with the genotype R/R in the disease group (5%) in respect to the normal healthy cohort (0.5%). Finally, the frequency of the PON55 heterozygotes L/M genotype was 29% in patients with CCMs and 4% in the healthy controls. The same trend was observed in PON55 homozygous M/M genotype frequency (CCMs 20% vs controls 10%). The present study aimed to investigate the possible association of GLO1 A111E, PON1 Q192R and L55M polymorphisms with the risk of CCMs. We found that individuals with the GLO1 A /E genotype, PON192/QR-RR genotypes and PON55/LM-MM genotypes had a significantly higher risk of CCMs compared with the other genotypes. However, because CCM is a heterogeneous disease, other additional factors might be involved in the initiation and progression of CCM disease.

Cheng TY, Makar KW, Neuhouser ML, et al.
Folate-mediated one-carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: Women's Health Initiative Observational Study.
Cancer. 2015; 121(20):3684-91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Investigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations.
METHODS: Two hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5'-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations.
RESULTS: Statistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P < .05). In addition, suggestive associations were noted for tagging SNPs in cystathionine-β-synthase (CBS), dihydrofolate reductase (DHFR), DNA (cytosine-5-)-methyltransferase 3β (DNMT3B), methionine adenosyltransferase I α (MAT1A), MTHFD1, and MTRR (nominal P < .05; adjusted P, not significant). Significant interactions between nutrient biomarkers and candidate polymorphisms were observed for 1) plasma/RBC folate and folate hydrolase 1 (FOLH1), paraoxonase 1 (PON1), transcobalamin II (TCN2), DNMT1, and DNMT3B; 2) plasma PLP and TYMS TS3; 3) plasma B12 and betaine-homocysteine S-methyltransferase 2 (BHMT2); and 4) homocysteine and methylenetetrahydrofolate reductase (MTHFR) and alanyl-transfer RNA synthetase (AARS).
CONCLUSIONS: Genetic variants in FOCM genes are associated with CRC risk among postmenopausal women. FOCM nutrients continue to emerge as effect modifiers of genetic influences on CRC risk.

An J, Lv J, Li A, et al.
Constitutive expression of Bcl-2 induces epithelial-Mesenchymal transition in mammary epithelial cells.
BMC Cancer. 2015; 15:476 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Bcl-2 (B cell lymphoma/leukemia gene-2) is the first proto-oncogene recognized to function by inhibiting programmed cell death/apoptosis. Although much is known about the anti-apoptotic ability of Bcl-2, little information is available concerning its function in other cellular processes, such as cell differentiation.
METHODS: In this study, stable cell lines from pre-malignant MCF10ATG3B mammary epithelial cells, a cell line derived from a human proliferative breast disease model, to express exogenous Bcl-2 was established. CMV promoter driven Bcl-2 expression vector or empty vector was transfected into MCF10ATG3B human mammary epithelial cells to investigate the effects of Bcl-2 on mammary epithelial cells. In addition, western blot and immunofluoresence staining were employed to testify the marker proteins of both mesenchymal and epithelial cells.
RESULTS: Unexpectedly, a dramatic change of phenotype from epithelial cells to fibroblast-like cells was observed in Bcl-2-transfected cells. Western blot analysis and immunofluoresence staining results demonstrated that the E-cadherin and desmoplakin, markers of epithelial cells, were downregulated in the Bcl-2-transfected cells. However, N-cadherin and vimentin, markers of mesenchymal cells, were upregulated in these cells. Redistributions of cytokeratin and beta-catenin were also observed in the Bcl-2-transfected cells. Our results further showed that the Bcl-2-transfected MCF10ATG3B cells retained some epithelial markers, such as epithelial specific antigen (ESA) and epithelial membrane antigen (EMA), indicating their epithelial origin. In addition, cell migration and invasion was substantially increased in Bcl-2 transfected cells.
CONCLUSION: Taken together, our results strongly indicate that in addition to its anti-apoptotic function, Bcl-2 is also involved in the epithelial-mesenchymal transition (EMT), a fundamental mechanism in normal morphogenesis and pathogenesis of some diseases.

Ma C, Ding YC, Yu W, et al.
MicroRNA-200c overexpression plays an inhibitory role in human pancreatic cancer stem cells by regulating epithelial-mesenchymal transition.
Minerva Med. 2015; 106(4):193-202 [PubMed] Related Publications
AIM: Cancer stem cells (CSCs) are believed to be the 'seed cell' in cancer recurrence and metastasis. MicroRNAs (miRNAs) have emerged as potential therapeutic candidates due to their ability to regulate the epithelial-mesenchymal transition (EMT). The goal of this study was to investigate the effect of miRNA-200c (miR-200c) on the EMT, tumorigenesis, colony formation, invasion and chemoresistance of human pancreatic cancer stem cells (PCSCs).
METHODS: PCSCs with CD24+CD44+ESA+ as the marker was sorted from PANC-1 cell line by fluorescence activated cell sorter (FACS). Quantitative real-time PCR (qRT-PCR) assay was used to detect the relative mRNA expression levels of miR-200c and EMT-associated phenotypes. Transfection of miR-200c mimic into PCSCs was performed to establish miR- 200c overexpressed cells. The assays of colony forming, cellular invasion and survival in vitro and tumor progression in vivo were performed.
RESULTS: Expression of miR-200c was significantly reduced in PCSCs compared with PANC-1 cells. However, the stable over expression of the miR-200c in the PCSCs resulted in a significant down-regulation of zinc-finger E-box binding homeobox 1 (ZEB1) and the Vimentin expression, an upregulation of the E-cadherin expression as well as a decrease of colony forming, chemoresistance and invasion in vitro and xenograft growth in vivo in nude mice by inhibition of the EMT.
CONCLUSION: Our study demonstrated that miR-200c may become a new therapeutic target for gene therapy in patients suffered from pancreatic cancer.

Zhang M, Xiong H, Fang L, et al.
Paraoxonase 1 (PON1) Q192R Gene Polymorphism and Cancer Risk: A Meta-Analysis Based on 30 Publications.
Asian Pac J Cancer Prev. 2015; 16(10):4457-63 [PubMed] Related Publications
Common genetic variation Q192R in the paraoxonase 1 (PON1) gene has been considered to be implicated in the development of many cancers. Nevertheless, results from the related studies were inconsistent. To elucidate the association, we performed a meta-analysis for 8,112 cases and 10,037 controls from 32 published case-control studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association by STATA 12.0 software. Overall, we revealed that the PON1-192R allele was associated with a reduced risk of the overall cancers. Moreover, in the stratified analysis by cancer types (breast cancer, prostate cancer, brain cancer etc.), the results showed that PON1-192R allele was associated with a decreased risk in breast cancer (R vs Q: OR=0.605, 95% CI=0.378-0.967, Pheterogeneity=0.000; RR vs QQ: OR=0.494, 95% CI=0.275-0.888, Pheterogeneity=0.002; RQ vs QQ: OR=0.465, 95% CI=0.259-0.835, Pheterogeneity=0.000; and RR+RQ vs QQ: OR=0.485, 95% CI=0.274-0.857, Pheterogeneity=0.000), and associated with prostate cancer in homozygote (RR vs QQ: OR=0.475, 95% CI=0.251- 0.897, Pheterogeneity=0.001) and recessive models (RR vs RQ+QQ: OR=0.379, 95% CI=0.169-0.853, Pheterogeneity=0.000), while an increased risk was identified in lymphoma (R vs Q: OR=1.537, 95% CI=1.246-1.896, Pheterogeneity=0.944; RR vs QQ: OR=2.987, 95% CI=1.861-4.795, Pheterogeneity=0.350; RR+RQ vs QQ: OR=1.354, 95% CI=1.021-1.796, Pheterogeneity=0.824; and RR vs RQ+QQ: OR=2.934, 95% CI=1.869-4.605, Pheterogeneity=0.433), and an increased risk in prostate cancer under heterozygote comparison (RQ vs QQ: OR=1.782, 95% CI=1.077-2.950, Pheterogeneity=0.000) and dominant models (RR+RQ vs QQ: OR=1.281, 95% CI=1.044-1.573, Pheterogeneity=0.056). When subgroup analysis that performed by the control source (hospital based or population based), a decreased risk of the overall cancers was revealed by homozygote (RR vs QQ: OR=0.601, 95% CI=0.366-0.987, Pheterogeneity=0.000) and dominant models (RR vs RQ+QQ: OR=0.611, 95% CI=0.384-0.973, Pheterogeneity=0.000) in hospital based group. Stratifying by ethnicity, a significantly reduced risk of the overall cancers under allele contrast model (R vs Q: OR=0.788, 95% CI=0.626-0.993, Pheterogeneity=0.000) was uncovered in Caucasian. In summary, these findings suggested that PON1 Q192R polymorphism was associated with a reduced risk of the overall cancers, nevertheless, it might increase cancer susceptibility of prostate and lymphoma risk. Large well-designed epidemiological studies will be continued on this issue of interest.

Dadachanji R, Shaikh N, Khavale S, et al.
PON1 polymorphisms are associated with polycystic ovary syndrome susceptibility, related traits, and PON1 activity in Indian women with the syndrome.
Fertil Steril. 2015; 104(1):207-16 [PubMed] Related Publications
OBJECTIVE: To investigate the association of paraoxonase 1 (PON1) polymorphisms (L55M and Q192R) with polycystic ovary syndrome (PCOS) susceptibility and its related traits in Indian women.
DESIGN: Case-control study.
SETTING: Academic research institute, infertility, and endocrinology clinics.
PATIENT(S): Controls (n = 326), women with PCOS (n = 482).
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): Genotypic and allelic frequency distribution, genotype-phenotype association, different PON1 activities (lactonase, arylesterase, and paraoxonase).
RESULT(S): The genotypic and allelic frequency distributions of the L55M polymorphism were significantly different between lean controls and lean women with PCOS, and this polymorphism reduced the risk of PCOS development in lean but not in obese Indian women. Furthermore, this polymorphism was significantly associated with decreased 2-hour glucose, apolipoprotein B, free and bioavailable T, and free androgen index concurrent with increased sex hormone-binding globulin (SHBG) and FSH levels only in lean women with PCOS. However, Q192R polymorphism showed comparable genotypic frequency distribution between controls and women with PCOS. PON1 lactonase and arylesterase activities were significantly decreased in women with PCOS compared with controls. PON1 polymorphisms were shown to influence its activities.
CONCLUSION(S): Our study showed that L55M, but not Q192R, polymorphism is significantly associated with reduced PCOS susceptibility only in lean women and also impacts glucose metabolism, lipid parameters, and hyperandrogenemia in them. Our study therefore suggests the possibility of differential genetic pathophysiology of PCOS between lean and obese women.

Yuan C, Yip SP, Wu VW, et al.
Association between genetic polymorphisms and carotid atherosclerosis in patients treated with radiotherapy for nasopharyngeal carcinoma.
Radiat Oncol. 2015; 10:39 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Radiotherapy (RT) of the neck is commonly given to nasopharyngeal carcinoma (NPC) patients for preventing cervical lymph node metastasis. However, neck RT may induce the development of carotid atherosclerosis. The mechanisms of radiation-induced carotid atherosclerosis are still unclear and no previous study has investigated the genetic involvement of radiation-induced carotid atherosclerosis. The present study aims to determine the association between genetic polymorphisms and carotid atherosclerosis in patients treated with RT for nasopharyngeal carcinoma.
METHODS: The present study recruited 128 post-RT NPC patients. Carotid plaque score was assessed using ultrasonography. Thirteen single nucleotide polymorphisms (SNPs) that affect the function of anti-atherosclerotic genes, including SOD2, SOD3, CAT, PON1, PPARG, ADIPOQ, IL10, TGFB1 and NOS3, were genotyped. Association between the 13 SNPs and carotid atherosclerosis was evaluated using multiple regression after adjustment for covariates (PLINK). Multiple testing was corrected using Benjamini-Hochberg step-up false discovery rate controlling procedure.
RESULTS: rs662 and rs705379 of PON1 were close to be significantly associated with carotid plaque score (Corrected P value, P cor  =0.0528 and P cor  =0.0842). When the two SNPs were combined together, TC haplotype in rs662-rs705379 of PON1 was significantly associated with higher carotid plaque score (P cor  < 0.05). None of the other SNPs showed significant association with carotid plaque score.
CONCLUSIONS: TC haplotype in rs662-rs705379 of PON1 is likely to be a genetic risk factor of carotid plaque score. Post-RT NPC patients with the TC haplotype may need earlier and more frequent carotid ultrasound examinations for early detection of carotid atherosclerosis.

Sai S, Wakai T, Vares G, et al.
Combination of carbon ion beam and gemcitabine causes irreparable DNA damage and death of radioresistant pancreatic cancer stem-like cells in vitro and in vivo.
Oncotarget. 2015; 6(8):5517-35 [PubMed] Free Access to Full Article Related Publications
We try to elucidate whether a carbon ion beam alone or in combination with gemcitabine has advantages over X-ray in targeting putative pancreatic cancer stem-like cells (CSCs) in vitro and in vivo. Colony, spheroid formation and tumorigenicity assays confirmed that CD44+/ESA+ cells sorted from PANC1 and PK45 cells have more CSC properties than CD44-/ESA- cells. The number of colonies and spheroids formed from CSCs after carbon ion beam irradiation was significantly reduced compared to after X-ray irradiation, and they were extremely highly suppressed when carbon ion beam combined with gemcitabine. The relative biological effectiveness (RBE) values for the carbon ion beam relative to X-ray at the D10 levels for CSCs were 2.23-2.66. Expressions of multiple cell death-related genes were remarkably highly induced, and large numbers of γH2AX foci in CSCs were formed after carbon ion beam combined with gemcitabine. The highly expressed CSC markers were significantly inhibited after 30 Gy of carbon ion beam and almost lost after 25 Gy carbon ion beam combined with 50 mg/kg gemcitabine. In conclusion, a carbon ion beam combined with gemcitabine has superior potential to kill pancreatic CSCs via irreparable clustered DSB compared to a carbon ion alone or X-rays combined with gemcitabine.

Attar R, Atasoy H, İnal-Gültekin G, et al.
The effects of PON1 gene Q192R variant on the development of uterine leiomyoma in Turkish patients.
In Vivo. 2015 Mar-Apr; 29(2):243-6 [PubMed] Related Publications
AIM: This study aimed to analyze the relation between uterine leiomyoma (ULM) patients and p.Q192R polymorphism.
MATERIALS AND METHODS: ULM patients (n=76) and healthy women (n=103) were recruited from the Yeditepe University, Department of Gynecology and Obstetrics. The genotype and allele distribution of p.Q192R was analyzed by polymerase chain reaction and restriction fragment length polymorphism methods. Genotype and allele frequencies between study groups were calculated by the chi-square (χ(2)) and Fischer's exact test.
RESULTS: The frequency of the B allele was lower in patients (p<0.001) and the AB genotype showed a decreased risk for ULM development (p<0.001). The variation was unrelated to ULM size and number. There was no significant difference between p.Q192R genotype frequencies and fibroid size and number.
CONCLUSION: The heterogeneous AB genotype of PON1 p.Q192R variation could be recognized as a low-risk parameter for the development of ULM in Turkish women.

Eom SY, Yim DH, Lee CH, et al.
Interactions between paraoxonase 1 genetic polymorphisms and smoking and their effects on oxidative stress and lung cancer risk in a Korean population.
PLoS One. 2015; 10(3):e0119100 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Few studies in epidemiology have evaluated the effects of gene-environment interaction on oxidative stress, even though this interaction is an important etiologic factor in lung carcinogenesis. We investigated the effects of the genetic polymorphisms of paraoxonase 1 (PON1), smoking, and the interaction between the two on lung cancer risk and oxidative stress.
METHODS: This study's subjects consisted of 416 newly diagnosed lung cancer patients and an equal number of matched controls. The GoldenGate assay was used for genotypic analyses of the PON1 gene. Urinary 8-hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid reactive substances levels were measured as indicators of oxidative stress.
RESULTS: The PON1 rs662 AA genotype showed a significantly lower risk of lung cancer than the GG genotype (OR = 0.60, 95% CI: 0.36-0.99). The protective effect of the PON1 rs662 AA genotype on lung cancer risk was limited to non-smokers. Lung cancer patients who had the rs662 A allele showed a dose-dependent association between smoking status and oxidative stress markers. Among non-smoking lung cancer patients, urinary 8-OHdG levels were significantly lower in individuals with the rs662 GA and AA genotypes than in those with the GG genotype. Furthermore, we found a significant interaction effect between PON1 rs662 and smoking status on urinary 8-OHdG levels in lung cancer patients.
CONCLUSIONS: Our results suggest that the protective effect of PON1 rs662 SNP against lung carcinogenesis and the induction of oxidative stress might be modulated by the interaction between PON1 genetic polymorphisms and tobacco smoking.

Ahmed NS, Shafik NM, Elraheem OA, Abou-Elnoeman SE
Association of paraoxonase-1(Q192R and L55M) gene polymorphisms and activity with colorectal cancer and effect of surgical intervention.
Asian Pac J Cancer Prev. 2015; 16(2):803-9 [PubMed] Related Publications
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related death. Oxidative DNA damage may contribute to cancer risk and the antioxidant paraoxonase is one endogenous free radical scavenger in the human body which could therefore exert an influeence.
PURPOSE: Aim of this study was to determine the role of serum arylesterase (ARE) and paraoxonase 1(PON1) activities in CRC patients and to find any association between (PON1) Q192R and L55M gene polymorphisms in CRC patients. Also the serum ARE and PON1 activities in CRC patients will be investigated before and after surgery Materials and Methods: This study involved a total of 50 patients with newly diagnosed CRC and 80 healthy controls. PON1 and ARE activities were determined using an enzymatic spectrophotometric method. PON1 Q192R and L55M gene polymorphisms were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) based restriction fragment analysis. The restriction enzyme AlwI was used to examine the Q192R polymorphism and Hsp92II for the L55M polymorphism.
RESULTS: Significant differences in the PON1 Q192R polymorphism were found between patients and controls. The Q allele was more frequent in the patient group than in controls, while the R allele was more frequent in the controls. Significant differences were found in the L55M polymorphism. Additionally, there were significant differences in L and M allele frequencies (p=0.001). The serum activities of PON1 and ARE were low in QQ and MM genotype.
CONCLUSIONS: serum PON1 and ARE activities were significantly lower in CRC patients compared to healthy subjects. The R allele may protect against colorectal cancer.

Zhang Y, Liu H, He J, et al.
Lactonase activity and status of paraoxonase 1 in Chinese women with polycystic ovarian syndrome.
Eur J Endocrinol. 2015; 172(4):391-402 [PubMed] Related Publications
OBJECTIVE: To study the relationship between the lactonase activities and status of paraoxonase 1 (PON1) and its association with the PON1 genetic polymorphisms in women with polycystic ovarian syndrome (PCOS).
DESIGN: A case-control study.
METHODS: A total of 455 PCOS patients and 441 control women were included in this study. The lactonase activities and concentrations of PON1 were assayed using 5-thiobutyl butyrolactone (TBBL) and 7-O-diethylphosphoryl-3-cyano-4-methyl-7-hydroxycoumarin (DEPCyMC) respectively. A normalized lactonase activity (NLA) was estimated based on the ratio of TBBLase:DEPCyMCase activity. The PON1 genotypes, serum malondialdehyde (MDA) levels and total antioxidant capacity were analyzed.
RESULTS: The lactonase activities and levels of PON1 were higher in PCOS patients than in the control women. However, the NLA did not significantly differ between groups. The -108C→T variation of the PON1 gene showed decreased lactonase activities and levels of PON1 in a genotype-dependent manner (CC>CT>TT); the 192Q→R variation of the PON1 gene showed increased PON1 lactonase activities and NLA; and the 55L→M variation of the PON1 gene showed decreased lactonase activities and levels of PON1 but an increased NLA. A multivariable regression analysis showed that the -108C/T, 192Q/R, and 55L/M variations of the PON1 gene, serum apolipoprotein A1, and MDA levels were significant predictors of PON1 lactonase activity, PON1 level, and NLA.
CONCLUSIONS: The serum lactonase activities and concentrations of PON1 are increased in PCOS patients. The increased oxidative stress and the -108C/T, 192Q/R, and 55L/M genetic polymorphisms of PON1 may be associated with these changes.

Geng R, Chen Z, Zhao X, et al.
Oxidative stress-related genetic polymorphisms are associated with the prognosis of metastatic gastric cancer patients treated with epirubicin, oxaliplatin and 5-fluorouracil combination chemotherapy.
PLoS One. 2014; 9(12):e116027 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Oxidative stress genes are related to cancer development and treatment response. In this study, we aimed to determine the predictive and prognostic roles of oxidative stress-related genetic polymorphisms in metastatic gastric cancer (MGC) patients treated with chemotherapy.
METHODS: In this retrospective study, we genotyped nine oxidative stress-related single nucleotide polymorphisms (SNPs) in NQO1, SOD2, SOD3, PON1, GSTP1, GSTT1, and NOS3 (rs1800566, rs10517, rs4880, rs1799895, rs662, rs854560, rs1695, rs2266637, rs1799983, respectively) in 108 consecutive MGC patients treated with epirubicin, oxaliplatin, and 5-fluorouracil (EOF) regimen as the first-line chemotherapy and analyzed the association between the genotypes and the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
RESULTS: We found that, in addition to a lower pathological grade (p = 0.017), NQO1 rs1800566 CT/TT genotype was an independent predictive factor of poor PFS (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.23-3.16; p = 0.005). PON1 rs662 AA/AG genotype was significantly associated with poor OS (HR = 1.95, 95% CI = 1.07-3.54; p = 0.029). No associations were detected between the nine SNPs and DCR.
CONCLUSIONS: NQO1 rs1800566 is an independent predictive factor of PFS for MGC patients treated with EOF chemotherapy, and PON1 rs662 is a noteworthy prognostic factor of OS. Information on oxidative stress-related genetic variants may facilitate optimization of individualized chemotherapy in clinical practice.

Pon CK, Firth SM, Baxter RC
Involvement of insulin-like growth factor binding protein-3 in peroxisome proliferator-activated receptor gamma-mediated inhibition of breast cancer cell growth.
Mol Cell Endocrinol. 2015; 399:354-61 [PubMed] Related Publications
We have previously reported that insulin-like growth factor binding protein-3 (IGFBP-3), a protein with dichotomous effects on both cell proliferation and cell survival, interacts with peroxisome proliferator-activated receptor gamma (PPARγ) and inhibits adipogenic PPARγ signaling. We now show that IGFBP-3 and PPARγ interact in breast cancer cells, through amino- and carboxyl-terminal residues of IGFBP-3. IGFBP-3 and the PPARγ ligands, rosiglitazone or 15-deoxy-Δ(12,14)-prostaglandin J2, separately inhibited the proliferation of MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cells. However, growth inhibition by IGFBP-3 and PPARγ ligand combined was greater than by either alone. Two IGFBP-3 mutants with reduced PPARγ binding caused no growth inhibition when used alone and abolished the inhibitory effect of rosiglitazone when used in combination with PPARγ ligand. Cell growth inhibition by PPARγ ligands was substantially blocked by IGFBP-3 siRNA and restored by exogenous IGFBP-3. We conclude that the interaction between IGFBP-3 and PPARγ is important for the growth-inhibitory effect of PPARγ ligands in human breast cancer cells, suggesting that IGFBP-3 expression by breast tumors may regulate their sensitivity toward PPARγ ligands.

Kim HY, Park JH, Won HY, et al.
CBX7 inhibits breast tumorigenicity through DKK-1-mediated suppression of the Wnt/β-catenin pathway.
FASEB J. 2015; 29(1):300-13 [PubMed] Related Publications
Polycomb protein chromobox homolog 7 (CBX7) is involved in several biologic processes including stem cell regulation and cancer development, but its roles in breast cancer remain unknown. Here, we demonstrate that CBX7 negatively regulates breast tumor initiation. CD44(+)/CD24(-)/ESA(+) breast stem-like cells showed diminished CBX7 expression. Furthermore, small hairpin RNA-mediated CBX7 knockdown in breast epithelial and cancer cells increased the CD44(+)/CD24(-)/ESA(+) cell population and reinforced in vitro self-renewal and in vivo tumor-initiating ability. Similarly, CBX7 overexpression repressed these effects. We also found that CBX7 inhibits the Wnt/β-catenin/T cell factor pathway by enhancing the expression of Dickkopf-1 (DKK-1), a Wnt antagonist. In particular, CBX7 increased DKK-1 transcription by cooperating with p300 acetyltransferase and subsequently enhancing the histone acetylation of the DKK-1 promoter. Furthermore, pharmacologic inhibition of DKK-1 in CBX7-overexpressing cells showed recovery of Wnt signaling and consequent rescue of the CD44(+)/CD24(-)/ESA(+) cell population. Taken together, these findings indicate that CBX7-mediated epigenetic induction of DKK-1 is crucial for the inhibition of breast tumorigenicity, suggesting that CBX7 could be a potential tumor suppressor in human breast cancer.

Pon JR, Marra MA
Driver and passenger mutations in cancer.
Annu Rev Pathol. 2015; 10:25-50 [PubMed] Related Publications
Next-generation sequencing has allowed identification of millions of somatic mutations and epigenetic changes in cancer cells. A key challenge in interpreting cancer genomes and epigenomes is distinguishing which genetic and epigenetic changes are drivers of cancer development. Frequency-based and function-based approaches have been developed to identify candidate drivers; we discuss the advantages and drawbacks of these methods as well as their latest refinements. We focus particularly on identification of the types of drivers most likely to be missed, such as genes affected by copy number alterations, mutations in noncoding regions, dysregulation of microRNA, epigenetic changes, and mutations in chromatin modifiers.

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