Research IndicatorsGraph generated 11 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 11 March, 2017 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: GPX2 (cancer-related)
Zmorzyński S, Świderska-Kołacz G, Koczkodaj D, Filip AASignificance of Polymorphisms and Expression of Enzyme-Encoding Genes Related to Glutathione in Hematopoietic Cancers and Solid Tumors.
Biomed Res Int. 2015; 2015:853573 [PubMed
] Free Access to Full Article Related Publications
Antioxidant compounds such as glutathione and its enzymes have become the focus of attention of medical sciences. Glutathione, a specific tripeptide, is involved in many intercellular processes. The glutathione concentration is determined by the number of GAG repeats in gamma-glutamylcysteine synthetase. GAG polymorphisms are associated with an increased risk of schizophrenia, berylliosis, diabetes, lung cancer, and nasopharyngeal tumors. Cancer cells with high glutathione concentration are resistant to chemotherapy treatment. The oxidized form of glutathione is formed by glutathione peroxidases (GPXs). The changes in activity of GPX1, GPX2, and GPX3 isoforms may be associated with the development of cancers, for example, prostate cancer or even colon cancer. Detoxification of glutathione conjugates is possible due to activity of glutathione S-transferases (GSTs). Polymorphisms in GSTM1, GSTP1, and GSTO1 enzymes increase the risk of developing breast cancer and hepatocellular carcinoma. Gamma-glutamyl transpeptidases (GGTs) are responsible for glutathione degradation. Increased activity of GGT correlates with adverse prognosis in patients with breast cancer. Studies on genes encoding glutathione enzymes are continued in order to determine the correlation between DNA polymorphisms in cancer patients.
Chang IW, Lin VC, Hung CH, et al.GPX2 underexpression indicates poor prognosis in patients with urothelial carcinomas of the upper urinary tract and urinary bladder.
World J Urol. 2015; 33(11):1777-89 [PubMed
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PURPOSE: Oxidative stress is believed to be one of the important etiologies in carcinogenesis that has not been systemically investigated in urothelial carcinoma (UC). Through data mining from a published transcriptomic database of UC of urinary bladders (UBUCs) (GSE31684), glutathione peroxidase 2 (GPX2) was identified as the most significant downregulated gene among those response to oxidative stress (GO:0006979). We therefore analyze GPX2 transcript and protein expressions and its clinicopathological significance.
METHODS: Real-time RT-PCR assay was used to detect GPX2 mRNA level in 20 fresh UBUC specimens. Immunohistochemistry was used to determine GPX2 protein expression in 340 urothelial carcinomas of upper tracts (UTUCs) and 295 UBUCs with mean/median follow-up of 44.7/38.9 and 30.8/23.1 months, respectively. Its expression status was further correlated with clinicopathological features and evaluated for its impact on disease-specific survival and metastasis-free survival (MeFS).
RESULTS: Decrease in GPX2 transcript level was associated with both higher pT and positive nodal status in 20 UBUCs (all p < 0.05). GPX2 protein underexpression was also significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular invasion, and frequent mitoses in both groups of UCs (all p < 0.05). GPX2 underexpression not only predicted dismal DDS and MeFS at univariate analysis, but also implicated worse DDS (UTUC, p = 0.002; UBUC, p = 0.029) and MeFS (UTUC, p = 0.001; UBUC, p = 0.032) in multivariate analysis.
CONCLUSIONS: GPX2 underexpression is associated with advanced tumor status and implicated unfavorable clinical outcome of UCs, suggesting its role in tumor progression and may serve as a theranostic biomarker of UCs.
Kim B, Kang S, Jeong G, et al.Identification and comparison of aberrant key regulatory networks in breast, colon, liver, lung, and stomach cancers through methylome database analysis.
PLoS One. 2014; 9(5):e97818 [PubMed
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Aberrant methylation of specific CpG sites at the promoter is widely responsible for genesis and development of various cancer types. Even though the microarray-based methylome analyzing techniques have contributed to the elucidation of the methylation change at the genome-wide level, the identification of key methylation markers or top regulatory networks appearing common in highly incident cancers through comparison analysis is still limited. In this study, we in silico performed the genome-wide methylation analysis on each 10 sets of normal and cancer pairs of five tissues: breast, colon, liver, lung, and stomach. The methylation array covers 27,578 CpG sites, corresponding to 14,495 genes, and significantly hypermethylated or hypomethylated genes in the cancer were collected (FDR adjusted p-value <0.05; methylation difference >0.3). Analysis of the dataset confirmed the methylation of previously known methylation markers and further identified novel methylation markers, such as GPX2, CLDN15, and KL. Cluster analysis using the methylome dataset resulted in a diagram with a bipartite mode distinguishing cancer cells from normal cells regardless of tissue types. The analysis further revealed that breast cancer was closest with lung cancer, whereas it was farthest from colon cancer. Pathway analysis identified that either the "cancer" related network or the "cancer" related bio-function appeared as the highest confidence in all the five cancers, whereas each cancer type represents its tissue-specific gene sets. Our results contribute toward understanding the essential abnormal epigenetic pathways involved in carcinogenesis. Further, the novel methylation markers could be applied to establish markers for cancer prognosis.
Wang S, Tu J, Zhou C, et al.The effect of Lfcin-B on non-small cell lung cancer H460 cells is mediated by inhibiting VEGF expression and inducing apoptosis.
Arch Pharm Res. 2015; 38(2):261-71 [PubMed
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Lfcin-B, an antimicrobial peptide found in various exocrine secretions of mammals, showed antitumor effects. However, the effect and relative mechanism of Lfcin-B on non-small cell lung cancer is unclear. In this study, assay of cell viability, quantitative real-time PCR, Western blot, annexin V/propidium iodide assay, flow cytometry and tumor-xenograft model were applied to elucidate the mechanism of Lfcin-B on non-small cell lung cancer NCI-H460 (H460) cells. Lfcin-B significantly suppressed the proliferation of H460 cells in vitro. Additionally, the transcription and translation of the VEGF gene in H460 cells were restrained after exposure to Lfcin-B. Moreover, the apoptosis of H460 cells was induced by Lfcin-B through stimulating caspase-3, caspase-9 and preventing survivin expression on both the transcription and translation level. Meanwhile, Lfcin-B increased the production of reactive oxygen species and suppressed the RNA of antioxidant enzymes (GPX1, GPX2, SOD3 and catalase) in H460 cells. Finally, Lfcin-B significantly prevented the tumor growth in the H460-bearing mice model. These results indicated that Lfcin-B could be a potential candidate for the treatment of lung cancer.
Naiki T, Naiki-Ito A, Asamoto M, et al.GPX2 overexpression is involved in cell proliferation and prognosis of castration-resistant prostate cancer.
Carcinogenesis. 2014; 35(9):1962-7 [PubMed
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There is a need for exploration of new therapeutic strategies that target distinct molecular mechanisms of castration-resistant prostate cancer (CRPC) because its emergence following androgen deprivation therapy is a major clinical problem. In this report, we investigated the role of glutathione peroxidase 2 (GPX2) in CRPC. GPX2 expression was analyzed in rat and human CRPC cells. Next, we determined the proliferation rate and level of reactive oxygen species (ROS) in GPX2-small interfering RNA (siRNA)-transfected CRPC cells. For in vivo analysis, siRNA-transfected cells were subcutaneously implanted into normal and castrated nude mice. Further, immunohistochemical and prognostic analyses of GPX2 were performed using human specimens. Silencing of GPX2 caused significant growth inhibition and increased intracellular ROS in both rat (PCai1) and human (PC3) CRPC cells. Flow cytometry and western blot analyses revealed that the decrease in proliferation rate of the GPX2-silenced cells was due to cyclin B1-dependent G2/M arrest. Furthermore, knockdown of Gpx2 inhibited tumor growth of PCai1 cells in castrated mice. Immunohistochemical analyses indicated that expression of GPX2 was significantly higher in residual cancer foci after neoadjuvant hormonal therapy than in hormone naive cancer foci. Moreover, patients with high GPX2 expression in biopsy specimen had significantly lower prostate-specific antigen recurrence-free survival and overall survival than those with no GPX2 expression. These findings suggest that GPX2 is a prognostic marker in CRPC and affects proliferation of prostate cancer under androgen depletion partially through protection against ROS signaling.
Selenoproteins are a class of proteins containing a selenocysteine residue, many of which have been shown to have redox functions, acting as antioxidants to decrease oxidative stress. Selenoproteins have previously been associated with risk of various cancers and redox-related diseases. In this study we evaluated possible associations between breast cancer risk and survival and single nucleotide polymorphisms (SNPs) in the selenoprotein genes GPX1, GPX2, GPX3, GPX4, SELS, SEP15, SEPN1, SEPP1, SEPW1, TXNRD1, and TXNRD2 among Hispanic/Native American (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Adaptive Rank Truncated Product (ARTP) analysis was used to determine both gene and pathway significance with these genes. The overall selenoprotein pathway PARTP was not significantly associated with breast cancer risk (PARTP = 0.69), and only one gene, GPX3, was of borderline significance for the overall population (PARTP =0.09) and marginally significant among women with 0-28% Native American (NA) ancestry (PARTP=0.06). The SEPP1 gene was statistically significantly associated with breast cancer risk among women with higher NA ancestry (PARTP=0.002) and contributed to a significant pathway among those women (PARTP=0.04). GPX1, GPX3, and SELS were associated with Estrogen Receptor-/Progesterone Receptor+ status (PARTP = 0.002, 0.05, and 0.01, respectively). Four SNPs (GPX3 rs2070593, rsGPX4 rs2074451, SELS rs9874, and TXNRD1 rs17202060) significantly interacted with dietary oxidative balance score after adjustment for multiple comparisons to alter breast cancer risk. GPX4 was significantly associated with breast cancer survival among those with the highest NA ancestry (PARTP = 0.05) only. Our data suggest that SEPP1 alters breast cancer risk among women with higher levels of NA ancestry.
BACKGROUND: Ovarian cancer is characterized by high rates of metastasis and therapeutic resistance. Many chemotherapeutic agents rely on the induction of oxidative stress to cause cancer cell death, thus targeting redox regulation is a promising strategy to overcome drug resistance.
METHODS: We have used a tetracycline-inducible Ets-1 overexpression model derived from 2008 ovarian cancer cells in the present study. To examine the role of Ets-1 in glutathione regulation we have measured intracellular reactive oxygen species and glutathione levels, as well as glutathione peroxidase enzyme activity. Glutathione synthesis was limited using transsulfuration or Sx(c)- pathway blocking agents, and glutamate release was measured to confirm Sx(c)- blockade. Cell viability following drug treatment was assessed via crystal violet assay. Oxidative stress was induced through glucose oxidase treatment, which produces hydrogen peroxide by glucose oxidation. The protein expressions of redox-related factors were measured through western blotting.
RESULTS: Overexpression of Ets-1 was associated with decreased intracellular ROS, concomitantly with increased intracellular GSH, GPX antioxidant activity, and Sx(c)- transporter activity. Under basal conditions, inhibition of the transsulfuration pathway resulted in decreased GSH levels and GPX activity in all cell lines, whereas inhibition of Sx(c)- by sulfasalazine decreased GPX activity in Ets-1-expressing cells only. However, under oxidative stress the intracellular GSH levels decreased significantly in correlation with increased Ets-1 expression following sulfasalazine treatment.
CONCLUSIONS: In this study we have identified a role for proto-oncogene Ets-1 in the regulation of intracellular glutathione levels, and examined the effects of the anti-inflammatory drug sulfasalazine on glutathione depletion using an ovarian cancer cell model. The findings from this study show that Ets-1 mediates enhanced Sx(c)- activity to increase glutathione levels under oxidative stress, suggesting that Ets-1 could be a promising putative target to enhance conventional therapeutic strategies.
Méplan C, Dragsted LO, Ravn-Haren G, et al.Association between polymorphisms in glutathione peroxidase and selenoprotein P genes, glutathione peroxidase activity, HRT use and breast cancer risk.
PLoS One. 2013; 8(9):e73316 [PubMed
] Free Access to Full Article Related Publications
Breast cancer (BC) is one of the most common cancers in women. Evidence suggests that genetic variation in antioxidant enzymes could influence BC risk, but to date the relationship between selenoproteins and BC risk remains unclear. In this report, a study population including 975 Danish cases and 975 controls matched for age and hormone replacement therapy (HRT) use was genotyped for five functional single nucleotide polymorphisms (SNPs) in SEPP1, GPX1, GPX4 and the antioxidant enzyme SOD2 genes. The influence of genetic polymorphisms on breast cancer risk was assessed using conditional logistic regression. Additionally pre-diagnosis erythrocyte GPx (eGPx) activity was measured in a sub-group of the population. A 60% reduction in risk of developing overall BC and ductal BC was observed in women who were homozygous Thr carriers for SEPP1 rs3877899. Additionally, Leu carriers for GPX1 Pro198Leu polymorphism (rs1050450) were at ∼2 fold increased risk of developing a non-ductal BC. Pre-diagnosis eGPx activity was found to depend on genotype for rs713041 (GPX4), rs3877899 (SEPP1), and rs1050450 (GPX1) and on HRT use. Moreover, depending on genotype and HRT use, eGPx activity was significantly lower in women who developed BC later in life compared with controls. Furthermore, GPx1 protein levels increased in human breast adenocarcinoma MCF7 cells exposed to β-estradiol and sodium selenite.In conclusion, our data provide evidence that SNPs in SEPP1 and GPX1 modulate risk of BC and that eGPx activity is modified by SNPs in SEPP1, GPX4 and GPX1 and by estrogens. Our data thus suggest a role of selenoproteins in BC development.
The selenoprotein glutathione peroxidase-2 (GPx2) appears to have a dual role in carcinogenesis. While it protected mice from colon cancer in a model of inflammation-triggered carcinogenesis (azoxymethane and dextran sodium sulfate treatment), it promoted growth of xenografted tumor cells. Therefore, we analyzed the effect of GPx2 in a mouse model mimicking sporadic colorectal cancer (azoxymethane-treatment only). GPx2-knockout (KO) and wild-type (WT) mice were adjusted to an either marginally deficient (-Se), adequate (+Se), or supranutritional (++Se) selenium status and were treated six times with azoxymethane (AOM) to induce tumor development. In the -Se and ++Se groups, the number of tumors was significantly lower in GPx2-KO than in respective WT mice. On the +Se diet, the number of dysplastic crypts was reduced in GPx2-KO mice. This may be explained by more basal and AOM-induced apoptotic cell death in GPx2-KO mice that eliminates damaged or pre-malignant epithelial cells. In WT dysplastic crypts GPx2 was up-regulated in comparison to normal crypts which might be an attempt to suppress apoptosis. In contrast, in the +Se groups tumor numbers were similar in both genotypes but tumor size was larger in GPx2-KO mice. The latter was associated with an inflammatory and tumor-promoting environment as obvious from infiltrated inflammatory cells in the intestinal mucosa of GPx2-KO mice even without any treatment and characterized as low-grade inflammation. In WT mice the number of tumors tended to be lowest in +Se compared to -Se and ++Se feeding indicating that selenium might delay tumorigenesis only in the adequate status. In conclusion, the role of GPx2 and presumably also of selenium depends on the cancer stage and obviously on the involvement of inflammation.
Suzuki S, Pitchakarn P, Ogawa K, et al.Expression of glutathione peroxidase 2 is associated with not only early hepatocarcinogenesis but also late stage metastasis.
Toxicology. 2013; 311(3):115-23 [PubMed
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Understanding of mechanisms of cancer progression is very important for reduction of cancer mortality. Of six rat hepatocellular carcinoma (HCC) cell lines, differing in their metastatic potential to the lung after inoculation into the tail vein of nude mice, the most metastatic featured particular overexpression of glutathione peroxidase 2 (GPX2). Therefore, we analyzed the influence of interference in highly metastatic L2 cells by siRNA transfection. Gpx2 siRNA significantly inhibited cell proliferation at 24 and 48h time points with induction of apoptosis but not cell cycle arrest. High expression of mutated p53 was detected in all HCC cell lines, with reduction in Gpx2 siRNA-transfected cells. Migration and invasion in vitro were also suppressed as compared to control siRNA-transfected cells and secretion of matrix metalloproteinase 9 was reduced. In vivo, the numbers and areas of metastatic nodules per area in the lungs were significantly reduced in the mice inoculated with Gpx2 siRNA-transfected cells as compared to control siRNA-transfected cells. In conclusion, expression of GPX2 is associated with cancer metastasis from rat HCCs both in vitro and in vivo. Together with immunohistochemical findings of elevated expression in rat and also human liver lesions, the results point to important roles in hepatocarcinogenesis.
BACKGROUND: Heavy alcohol consumption increases risk of developing squamous cell carcinoma of the head and neck (SCCHN). Alcohol metabolism to cytotoxic and mutagenic intermediates acetaldehyde and reactive oxygen species is critical for alcohol-drinking-associated carcinogenesis. We hypothesized that polymorphisms in alcohol metabolism-related and antioxidant genes influence SCCHN survival.
METHODS: Interview and genotyping data (64 polymorphisms in 12 genes) were obtained from 1227 white and African-American cases from the Carolina Head and Neck Cancer Epidemiology study, a population-based case-control study of SCCHN conducted in North Carolina from 2002 to 2006. Vital status, date and cause of death through 2009 were obtained from the National Death Index. Kaplan-Meier log-rank tests and adjusted hazard ratios were calculated to identify alleles associated with survival.
RESULTS: Most tested SNPs were not associated with survival, with the exception of the minor alleles of rs3813865 and rs8192772 in CYP2E1. These were associated with poorer cancer-specific survival (HRrs3813865, 95% CI=2.00, 1.33-3.01; HRrs8192772, 95% CI=1.62, 1.17-2.23). Hazard ratios for 8 additional SNPs in CYP2E1, GPx2, SOD1, and SOD2, though not statistically significant, were suggestive of differences in allele hazards for all-cause and/or cancer death. No consistent associations with survival were found for SNPs in ADH1B, ADH1C, ADH4, ADH7, ALDH2, GPx2, GPx4, and CAT.
CONCLUSIONS: We identified some polymorphisms in alcohol and oxidative stress metabolism genes that influence survival in subjects with SCCHN. Previously unreported associations of SNPs in CYP2E1 warrant further investigation.
Shahdoust M, Hajizadeh E, Mozdarani H, Chehrei AFinding genes discriminating smokers from non-smokers by applying a growing self-organizing clustering method to large airway epithelium cell microarray data.
Asian Pac J Cancer Prev. 2013; 14(1):111-6 [PubMed
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BACKGROUND: Cigarette smoking is the major risk factor for development of lung cancer. Identification of effects of tobacco on airway gene expression may provide insight into the causes. This research aimed to compare gene expression of large airway epithelium cells in normal smokers (n=13) and non-smokers (n=9) in order to find genes which discriminate the two groups and assess cigarette smoking effects on large airway epithelium cells.
MATERIALS AND METHODS: Genes discriminating smokers from non-smokers were identified by applying a neural network clustering method, growing self-organizing maps (GSOM), to microarray data according to class discrimination scores. An index was computed based on differentiation between each mean of gene expression in the two groups. This clustering approach provided the possibility of comparing thousands of genes simultaneously.
RESULTS: The applied approach compared the mean of 7,129 genes in smokers and non-smokers simultaneously and classified the genes of large airway epithelium cells which had differently expressed in smokers comparing with non-smokers. Seven genes were identified which had the highest different expression in smokers compared with the non-smokers group: NQO1, H19, ALDH3A1, AKR1C1, ABHD2, GPX2 and ADH7. Most (NQO1, ALDH3A1, AKR1C1, H19 and GPX2) are known to be clinically notable in lung cancer studies. Furthermore, statistical discriminate analysis showed that these genes could classify samples in smokers and non-smokers correctly with 100% accuracy. With the performed GSOM map, other nodes with high average discriminate scores included genes with alterations strongly related to the lung cancer such as AKR1C3, CYP1B1, UCHL1 and AKR1B10.
CONCLUSIONS: This clustering by comparing expression of thousands of genes at the same time revealed alteration in normal smokers. Most of the identified genes were strongly relevant to lung cancer in the existing literature. The genes may be utilized to identify smokers with increased risk for lung cancer. A large sample study is now recommended to determine relations between the genes ABHD2 and ADH7 and smoking.
BACKGROUND: While several studies showed that selenium may prevent prostate cancer (PCa), few studies have evaluated variation in selenoenzyme genes in relation to PCa risk and survival.
METHODS: We studied common variants in seven selenoenzymes genes in relation to risk of PCa and PCa-specific mortality (PCSM). In a population-based case-control study of men of European ancestry (1,309 cases, 1,266 controls), we evaluated 35 common, tagging single nucleotide polymorphisms (SNPs) in GPX1 (n = 2), GPX2 (n = 4), GPX3 (n = 6), GPX4 (n = 6), SEP15 (n = 4), SEPP1 (n = 6), and TXNRD1 (n = 7) in relation to PCa risk, and among cases, associations between these variants and risk of PCSM. We used logistic regression and Cox proportional hazards regression to estimate the relative risk of PCa and PCSM, respectively.
RESULTS: Of the SNPs examined, only GPX1 rs3448 was associated with overall PCa risk with an odds ratio of 0.62 for TT versus CC (95% confidence interval, 0.44-0.88). SNPs in GPX2, GPX3, GPX4, SEP15, and SEPP1 had different risk estimates for PCa in subgroups based on stage and grade. We observed associations between SNPs in GPX4, and TXNRD1 and risk of PCSM. None of these associations, however, remained significant after adjustment for multiple comparisons.
CONCLUSIONS: We found evidence that genetic variation in a subset of selenoenzyme genes may alter risk of PCa and PCSM. These results need validation in additional subsets.
Kipp AP, Müller MF, Göken EM, et al.The selenoproteins GPx2, TrxR2 and TrxR3 are regulated by Wnt signalling in the intestinal epithelium.
Biochim Biophys Acta. 2012; 1820(10):1588-96 [PubMed
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BACKGROUND: The glutathione peroxidase 2 (GPx2) is expressed at crypt bases of the intestinal epithelium and in tumour tissue. The GPx2 promoter is activated by the Wnt pathway, which might be the reason for the specific expression pattern of GPx2. Together with additional selenoproteins, thioredoxin reductases TrxR2 and TrxR3, which are putative Wnt targets based on microarray analysis, Wnt-dependent GPx2 expression was analysed.
METHODS: Two cell culture models for either an activated (3T3 cells with Wnt3a overexpression) or an inhibited Wnt pathway (HT-29 APC cells) were analysed. To provide physiological relevance, crypt base epithelial cells of the jejunum and colon of mice were compared to cells of the villus or crypt table, respectively. In addition, β-catenin was deleted in crypt base cells ex vivo.
RESULTS: In cancer cell lines, the endogenous expression of all three selenoproteins was consistently dependent on Wnt pathway activity. Expression was higher in the proliferative crypt compartment, where also the Wnt pathway is active. An inducible knockout of β-catenin in isolated colonic crypt base cells reduced basal GPx2 expression. We, thus, demonstrated the regulation of GPx2 expression by the Wnt pathway in vitro and in vivo. Furthermore, the selenoproteins TrxR2 and TrxR3 have been identified as novel Wnt targets. This may imply a role of GPx2, TrxR2 and TrxR3 in proliferation, apoptosis and, therefore, also during cancer development.
GENERAL SIGNIFICANCE: Selenium which is essential for the biosynthesis of Wnt-dependent selenoproteins might be important for the renewal of the intestinal epithelium and during carcinogenesis.
Ziskin JL, Dunlap D, Yaylaoglu M, et al.In situ validation of an intestinal stem cell signature in colorectal cancer.
Gut. 2013; 62(7):1012-23 [PubMed
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OBJECTIVE: Wnt/Tcf, Lgr5, Ascl2 and/or Bmi1 signalling is believed to define the mouse intestinal stem cell niche(s) from which adenomas arise. The aim of this study was to determine the relevance of these putative intestinal stem cell markers to human colorectal cancer.
DESIGN: 19 putative intestinal stem cell markers, including Ascl2 and Lgr5, were identified from published data and an evaluation of a human colorectal gene expression database. Associations between these genes were assessed by isotopic in situ hybridisation (ISH) in 57 colorectal adenocarcinomas. Multiplex fluorescent ISH and chromogenic non-isotopic ISH were performed to confirm expression patterns. The prognostic significance of Lgr5 was assessed in 891 colorectal adenocarcinomas.
RESULTS: Ascl2 and Lgr5 were expressed in 85% and 74% of cancers respectively, and expression was positively correlated (p=0.003). Expression of Bmi1 was observed in 47% of cancers but was very weak in 98% of cases with expression. Both Ascl2 and/or Lgr5 were positively correlated with the majority of genes in the signature but neither was correlated with Cdk6, Gpx2, Olfm4 or Tnfrsf19. Lgr5 did not have prognostic significance.
CONCLUSION: These data suggest that 74-85% of colorectal cancers express a Lgr5/Ascl2 associated signature and support the hypothesis that they derive from Lgr5(+)/Ascl2(+) crypt stem cells, not Bmi1(+) stem cells. However, Olfm4 was not found to be a useful marker of Lgr5(+) cells in normal colon or tumours. In this large series, Lgr5 expression is not associated with increased tumour aggressiveness, as might be expected from a cancer stem cell marker.
Barrera LN, Cassidy A, Johnson IT, et al.Epigenetic and antioxidant effects of dietary isothiocyanates and selenium: potential implications for cancer chemoprevention.
Proc Nutr Soc. 2012; 71(2):237-45 [PubMed
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There is evidence from epidemiological studies suggesting that increased consumption of cruciferous vegetables may protect against specific cancers more effectively than total fruit and vegetable intake. These beneficial effects are attributed to the glucosinolate breakdown products, isothiocyanates (ITC). Similarly, selenium (Se) consumption has also been inversely associated with cancer risk and as an integral part of many selenoproteins may influence multiple pathways in the development of cancer. This paper will briefly review the current state of knowledge concerning the effect of Se and ITC in cancer development with a particular emphasis on its antioxidant properties, and will also address whether alterations in DNA methylation may be a potential mechanism whereby these dietary constituents protect against the carcinogenic process. Furthermore, we will discuss the advantages of combining ITC and Se to benefit from their complementary mechanisms of action to potentially protect against the alterations leading to neoplasia. Based on this review it may be concluded that an understanding of the impact of ITC and Se on aberrant DNA methylation in relation to factors modulating gene-specific and global methylation patterns, in addition to the effect of these food constituents as modulators of key selenoenzymes, such as gastrointestinal glutathione peroxidase-2 (GPx2) and thioredoxin reductase-1 (TrxR1), may provide insights into the potential synergy among various components of a plant-based diet that may counteract the genetic and epigenetic alterations that initiate and sustain neoplasia.
Glutathione peroxidases (GPXs) are selenium-dependent enzymes that reduce and, thus, detoxify hydrogen peroxide and a wide variety of lipid hydroperoxides. We investigated tagSNPs in GPX1-4 in relation to colorectal neoplasia in three independent study populations capturing the range of colorectal carcinogenesis from adenoma to cancer. A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r(2) ≥ 0.90, MAF ≥ 4%) identified 21 tagSNPs. We used an identical Illumina platform to genotype GPX SNPs in three population-based case-control studies of colon cancer (1,424 cases/1,780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). For gene-level associations, we conducted principal component analysis (PCA); multiple logistic regression was used for single SNPs. Analyses were adjusted for age, sex, and study center and restricted to non-Hispanic white participants. Analyses of cancer endpoints were stratified by molecular subtypes. Without correction for multiple testing, one polymorphism in GPX2 and three polymorphisms in GPX3 were associated with a significant risk reduction for rectal cancer at α = 0.05, specifically for rectal cancers with TP53 mutations. The associations regarding the three polymorphisms in GPX3 remained statistically significant after adjustment for multiple comparisons. The PCA confirmed an overall association of GPX3 with rectal cancer (P = 0.03). No other statistically significant associations were observed. Our data provide preliminary evidence that genetic variability in GPX3 contributes to risk of rectal cancer but not of colon cancer and thus provide additional support for differences in underlying pathogenetic mechanisms for colon and rectal cancer.
Hakenewerth AM, Millikan RC, Rusyn I, et al.Joint effects of alcohol consumption and polymorphisms in alcohol and oxidative stress metabolism genes on risk of head and neck cancer.
Cancer Epidemiol Biomarkers Prev. 2011; 20(11):2438-49 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Single-nucleotide polymorphisms (SNP) in alcohol metabolism genes are associated with squamous cell carcinoma of the head and neck (SCCHN) and may influence cancer risk in conjunction with alcohol. Genetic variation in the oxidative stress pathway may impact the carcinogenic effect of reactive oxygen species produced by ethanol metabolism. We hypothesized that alcohol interacts with these pathways to affect SCCHN incidence.
METHODS: Interview and genotyping data for 64 SNPs were obtained from 2,552 European- and African-American subjects (1,227 cases and 1,325 controls) from the Carolina Head and Neck Cancer Epidemiology Study, a population-based case-control study of SCCHN conducted in North Carolina from 2002 to 2006. We estimated ORs and 95% confidence intervals (CI) for SNPs and haplotypes, adjusting for age, sex, race, and duration of cigarette smoking. P values were adjusted for multiple testing using Bonferroni correction.
RESULTS: Two SNPs were associated with SCCHN risk: ADH1B rs1229984 A allele (OR = 0.7; 95% CI, 0.6-0.9) and ALDH2 rs2238151 C allele (OR = 1.2; 95% CI, 1.1-1.4). Three were associated with subsite tumors: ADH1B rs17028834 C allele (larynx, OR = 1.5; 95% CI, 1.1-2.0), SOD2 rs4342445 A allele (oral cavity, OR = 1.3; 95% CI, 1.1-1.6), and SOD2 rs5746134 T allele (hypopharynx, OR = 2.1; 95% CI, 1.2-3.7). Four SNPs in alcohol metabolism genes interacted additively with alcohol consumption: ALDH2 rs2238151, ADH1B rs1159918, ADH7 rs1154460, and CYP2E1 rs2249695. No alcohol interactions were found for oxidative stress SNPs.
CONCLUSIONS AND IMPACT: Previously unreported associations of SNPs in ALDH2, CYP2E1, GPX2, SOD1, and SOD2 with SCCHN and subsite tumors provide evidence that alterations in alcohol and oxidative stress pathways influence SCCHN carcinogenesis and warrant further investigation.
Hu Y, McIntosh GH, Le Leu RK, et al.The influence of selenium-enriched milk proteins and selenium yeast on plasma selenium levels and rectal selenoprotein gene expression in human subjects.
Br J Nutr. 2011; 106(4):572-82 [PubMed
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Certain forms of dietary Se may have advantages for improving human Se status and regulating the risk for disease, such as cancers, including colorectal cancer (CRC). The present study compared the effects of a Se-enriched milk protein (dairy-Se) with a Se-rich yeast (yeast-Se) on plasma Se levels and rectal selenoprotein gene expression since we reasoned that if these genes were not regulated, there was little potential for regulating the risk for CRC in this organ. A total of twenty-three healthy volunteers with plasma Se in the lower half of the population range were supplemented with dairy-Se (150 μg/d) or yeast-Se (150 μg/d) for 6 weeks, followed by 6 weeks of washout period. Blood was sampled every 2 weeks, and rectal biopsies were obtained before and after Se supplementation and after the washout period. Plasma Se levels and glutathione peroxidase (GPx) activity, and rectal mRNA of selenoprotein P (SeP), cytosolic GPx-1 (GPx-1), gastrointestinal GPx-2 (GPx-2) and thioredoxin reductase-1 (TrxR-1) were measured. Plasma Se levels increased rapidly in both Se groups (P < 0·001); plasma GPx activity was not significantly changed. Rectal SeP mRNA increased at 6 weeks compared with baseline in both Se groups (P < 0·05); only dairy-Se resulted in a sustained elevation of SeP after the washout period (P < 0·05). Rectal GPx-1 and GPx-2 mRNA were higher with dairy-Se (P < 0·05) than with yeast-Se at 6 weeks. In conclusion, three rectal selenoprotein mRNA were differentially regulated by dairy-Se and yeast-Se. Changes in rectal selenoproteins are not predicted by changes in plasma Se; dairy-Se effectively regulates the expression of several rectal selenoproteins of relevance to the risk for CRC.
Aberrant micro RNA (miRNA) expression has been implicated in the pathogenesis of cancer. Recent studies have shown that the miR-17-92 cluster is overexpressed in many types of cancer. The oncogenic function of mature miRNAs encoded by the miR-17-92 cluster has been identified from the 5' arm of six precursors. However, the function of the miRNAs produced from the 3' arm of these precursors remains unknown. The present study demonstrates that miR-17* is able to suppress critical primary mitochondrial antioxidant enzymes, such as manganese superoxide dismutase (MnSOD), glutathione peroxidase-2 (GPX2) and thioredoxin reductase-2 (TrxR2). Transfection of miR-17* into prostate cancer PC-3 cells significantly reduces levels of the three antioxidant proteins and activity of the luciferase reporter under the control of miR-17* binding sequences located in the 3'-untranslated regions of the three target genes. Disulfiram (DSF), a dithiolcarbomate drug shown to have an anticancer effect, induces the level of mature miR-17* and cell death in PCa cells, which can be attenuated by transfection of antisense miR-17*. Increasing miR-17* level in PC-3 cells by a Tet-on based conditional expression system markedly suppresses its tumorigencity. These results suggest that miR-17* may suppress tumorigenicity of prostate cancer through inhibition of mitochondrial antioxidant enzymes.
Gao K, Lockwood WW, Li J, et al.Genomic analyses identify gene candidates for acquired irinotecan resistance in melanoma cells.
Int J Oncol. 2008; 32(6):1343-9 [PubMed
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Efficacy of camptothecins (CPTs) such as irinotecan has been recognized in chemotherapy of cancers including melanoma. However, the majority of responding patients will gradually acquire drug resistance. Little is known of the genes responsible for the acquired CPT-resistance in cancer. To gain global insight into acquired CPT-resistance, we established irinotecan-resistant clones derived from melanoma cells and compared their whole genomes by high resolution array-CGH. A novel gain at 14q23.2-31.1 was revealed by alignment of whole genome profiles of parental cell line and irinotecan-resistant clones. Further analysis of this amplicon indicates that it encompassed genes involved in DNA repair (RAD51L, MLH3), reactive oxygen species (GPX2, CSTZ1, NGB, RDH11, ZADH1), and transportome (ABCD4, ATP6V1D, SLC10A6). Moreover, losses were also detected at the loci of topoisomerases (TOP1, SPO11, TOP3B) as well as at the loci of genes guarding chromosomal stability (TP53, ZW10, H2AFX, CHK1, CCDN1, MCM5, CENPB, DNMT3B), which would facilitate the development of drug resistance. Furthermore, quantitative real-time PCR demonstrated that mRNA changes of selected novel genes (CENPB, H2AFX, MCM5, ZADH1 and NGB) in irinotecan-resistant clones vs. parental clone were in agreement with array-CGH results. Taken together, our data suggest that genes involved in genome stability may greatly contribute to the development of CPTs-resistance. In addition, genes located at 14q23.3-31.1 would be promising targets to overcome acquired CPT-resistance in melanoma.
Peters U, Chatterjee N, Hayes RB, et al.Variation in the selenoenzyme genes and risk of advanced distal colorectal adenoma.
Cancer Epidemiol Biomarkers Prev. 2008; 17(5):1144-54 [PubMed
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BACKGROUND: Epidemiologic and animal studies provide evidence for a chemopreventive effect of selenium on colorectal cancer, which may be mediated by the antioxidative and anti-inflammatory properties of selenoenzymes. We therefore investigated whether genetic variants in selenoenzymes abundantly expressed in the colon are associated with advanced colorectal adenoma, a cancer precursor.
METHODS: Cases with a left-sided advanced adenoma (n = 772) and matched controls (n = 777) screen negative for polyps based on sigmoidoscopy examination were randomly selected from participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The underlying genetic variation was determined by resequencing. We genotyped 44 tagging single nucleotide polymorphisms (SNP) in six genes [glutathione peroxidase 1-4 (GPX1, GPX2, GPX3, and GPX4), selenoprotein P (SEPP1), and thioredoxin reductase 1 (TXNRD1)] to efficiently predict common variation across these genes.
RESULTS: Four variants in SEPP1 were significantly associated with advanced adenoma risk. A rare variant in the 5' region of SEPP1 (-4166C>G) was present in nine cases but in none of the controls (exact P = 0.002). Three SNPs located in the 3' region of SEPP1, which is overlapping with the promoter region of an antisense transcript, were significantly associated with adenoma risk: homozygotes at two SEPP1 loci (31,174 bp 3' of STP A>G and 43,881 bp 3' of STP G>A) were associated with increased adenoma risk [odds ratio (OR), 1.48; 95% confidence interval (95% CI), 1.00-2.19 and OR, 1.53; 95% CI, 1.05-2.22, respectively] and the variant SEPP1 44,321 bp 3' of STP C>T was associated with a reduced adenoma risk (CT versus CC OR, 0.85; 95% CI, 0.63-1.15). Furthermore, we observed a significant 80% reduction for advanced colorectal adenoma risk for carriers of the variant allele at TXNRD1 IVS1-181C>G (OR, 0.20; 95% CI, 0.07-0.55; P trend = 0.004). Consistent with the individual SNP results, we observed a significant overall association with adenoma risk for SEPP1 and TXNRD1 (global P = 0.02 and 0.008, respectively) but not for the four GPX genes.
CONCLUSION: Our study suggests that genetic variants at or near the SEPP1 and TXNRD1 loci may be associated with advanced colorectal adenoma. As this is the first study to comprehensively investigate this hypothesis, confirmation in independent study populations is needed.
Banning A, Florian S, Deubel S, et al.GPx2 counteracts PGE2 production by dampening COX-2 and mPGES-1 expression in human colon cancer cells.
Antioxid Redox Signal. 2008; 10(9):1491-500 [PubMed
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GPx2, the gastrointestinal glutathione peroxidase, is a selenoprotein predominantly expressed in the intestine. An anti-inflammatory and anticarcinogenic potential has been inferred from the development of colitis and intestinal cancer in GPx1 and GPx2 double knockout mice. Further, induction by Nrf2 activators classifies GPx2 as a protective enzyme. In contrast, enhanced COX-2 expression is consistently associated with inflammation. The antagonistic roles and an intriguing co-localization of GPx2 and COX-2 prompted us to investigate their possible mutual regulation. Both enzymes were upregulated in tissues of patients with colorectal cancer and colitis, and co-localized in the endoplasmic reticulum. A stable knockdown of GPx2 in HT-29 cells by siRNA resulted in a high basal and IL-1-induced expression of COX-2 and mPGES-1, enzymes required for the production of the pro-inflammatory PGE(2). Accordingly, si-GPx2 cells released high concentrations of PGE(2). Observed effects were specific for GPx2, since COX-2 and mPGES-1 expression was not affected by selenium-deprivation which resulted in the disappearance of GPx1. It is concluded that GPx2 by compartmentalized removal of hydroperoxides silences COX-2 activity and suppresses PGE(2)-dependent COX-2 expression. Thus, GPx2 may prevent undue responses to inflammatory stimuli and, in consequence, inflammation-driven initiation of carcinogenesis.
Ogawa R, Ishiguro H, Kuwabara Y, et al.Identification of candidate genes involved in the radiosensitivity of esophageal cancer cells by microarray analysis.
Dis Esophagus. 2008; 21(4):288-97 [PubMed
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Radiotherapy plays a key role in the control of tumor growth in esophageal cancer patients. To identify the patients who will benefit most from radiation therapy, it is important to know the genes that are involved in the radiosensitivity of esophageal cancer cells. Hence, we examined the global gene expression in radiosensitive and radioresistant esophageal squamous cell carcinoma cell lines. Radiosensitivities of 13 esophageal cancer cell lines were measured. RNA was extracted from each esophageal cancer cell line and a normal esophageal epithelial cell line, and the global gene expression profiles were analyzed using a 34 594-spot oligonucleotide microarray. In the clonogenic assay, one cell line (TE-11) was identified to be highly sensitive to radiation, while the other cell lines were found to be relatively radioresistant. We identified 71 candidate genes that were differentially expressed in TE-11 by microarray analysis. The up-regulated genes included CABPR, FABP5, DSC2, GPX2, NME, CBR3, DOCK8, and ABCC5, while the down-regulated genes included RPA1, LDOC1, NDN, and SKP1A. Our investigation provided comprehensive information on genes related to radiosensitivity of esophageal cancer cells; this information can serve as a basis for further functional studies.
Naiki-Ito A, Asamoto M, Hokaiwado N, et al.Gpx2 is an overexpressed gene in rat breast cancers induced by three different chemical carcinogens.
Cancer Res. 2007; 67(23):11353-8 [PubMed
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Gene expression alterations are essential for the process of carcinogenesis. A carcinogen may have specific mechanisms for inducing tumors, which may involve inducing characteristic gene expression alterations. In this study, we attempted to identify genes crucial for mammary carcinogenesis. For this purpose, we used human c-Ha-ras proto-oncogene transgenic rats (Hras128), which are highly sensitive to mammary carcinogens including N-methyl-N-nitrosourea, 7,12-dimethyl benz[a]anthracene, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. DNA microarray analysis revealed that glutathione peroxidase 2 (Gpx2) was commonly up-regulated in the mammary carcinomas induced by the three different carcinogens, and its up-regulation was confirmed by quantitative reverse transcriptase-PCR and Western blotting analysis. In addition, expression of GPX2 was recognized in all 41 immunohistochemically examined cases of human breast cancer. Forced suppression of GPX2 expression by siRNA resulted in significant growth inhibition in both rat and human mammary carcinoma cell lines with wild-type p53 cells. Thus, these data suggested that GPX2 may be involved in mammary carcinogenesis and cell proliferation in both rats and humans, indicating that GPX2 may be a novel target for the prevention and therapy of breast cancer.
Murphy SJ, Hughes AE, Patterson CC, et al.A population-based association study of SNPs of GSTP1, MnSOD, GPX2 and Barrett's esophagus and esophageal adenocarcinoma.
Carcinogenesis. 2007; 28(6):1323-8 [PubMed
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Oxidative stress appears to be important in the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Single-nucleotide polymorphisms (SNPs) of antioxidant enzyme genes may play a part in determining individual susceptibility to these diseases. The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study is a population-based, case-control study of BE and EAC in Ireland. DNA from EAC (n = 207), BE (> or =3 cm BE at endoscopy with specialized intestinal metaplasia on biopsy, n = 189) and normal population controls (n = 223) were analyzed. Several SNPs spanning the genes for glutathione S-transferase P1 (GSTP1), manganese superoxide dismutase (MnSOD) and glutathione peroxidase 2 (GPX2) were genotyped using multiplex polymerase chain reaction and SNaPshottrade mark. The chi(2) test was used to compare genotype and allele frequencies between case and control subjects. Linkage disequilibrium between SNPs was quantified using Lewontin's D' value and haplotype frequency estimates obtained using Haploview. Eleven SNPs were genotyped (six for GSTP1, three for MnSOD and two for GPX2); all were in Hardy-Weinberg equilibrium. None was significantly associated with EAC or BE even before Bonferroni correction. Odds ratios for EAC for individual SNPs ranged from 0.68 [95% confidence interval (CI) 0.43-1.08] to 1.25 (95% CI 0.73-2.16), and for BE from 0.84 (95% CI 0.52-1.30) to 1.30 (95% CI 0.85-1.97). SNPs in all three genes were in strong linkage disequilibrium (D' > 0.887) but haplotype analysis did not show any significant association with EAC or BE. SNPs involving the GSTP1, MnSOD and GPX2 genes were not associated with BE or EAC. Further studies aimed at identifying susceptibility genes should focus on different antioxidant genes or different pathways.
Brigelius-Flohé R, Banning APart of the series: from dietary antioxidants to regulators in cellular signaling and gene regulation. Sulforaphane and selenium, partners in adaptive response and prevention of cancer.
Free Radic Res. 2006; 40(8):775-87 [PubMed
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The association of decreased cancer risk with intake of cruciferous vegetables and selenium is stronger than that reported for fruits and vegetables in general. An active constituent in cruciferae is sulforaphane. Chemopreventive effects of both, sulforaphane and selenium have been attributed to an antioxidant action which certainly is too simplicistic. Sulforaphane induces via activation of the Nrf2/Keap1 system phase 2 enzymes that protect against carcinogens and oxidants. Induced enzymes comprise the selenoproteins thioredoxin reductase-1 (TrxR1) and gastrointestinal glutathione peroxidase (GI-GPx, GPx2), which contain antioxidant response elements (ARE) in their promoter regions. Translational realisation of the enhanced transcripts depends on adequate selenium supply, which explains the synergism of Nrf2 activators and selenium. Regarding tumorigenesis the role of TrxR1 is ambiguous: it is essential for fast tumor cell growth but also diminishes vascularisation of tumors. The anticarcinogenic role of GI-GPx is evident from enhanced gastrointestinal tumor formation in gpx2/gpx1 double KO mice.
Woenckhaus M, Klein-Hitpass L, Grepmeier U, et al.Smoking and cancer-related gene expression in bronchial epithelium and non-small-cell lung cancers.
J Pathol. 2006; 210(2):192-204 [PubMed
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Tobacco smoking is the leading cause of lung cancer worldwide. Gene expression in surgically resected and microdissected samples of non-small-cell lung cancers (18 squamous cell carcinomas and nine adenocarcinomas), matched normal bronchial epithelium, and peripheral lung tissue from both smokers (n = 22) and non-smokers (n = 5) was studied using the Affymetrix U133A array. A subset of 15 differentially regulated genes was validated by real-time PCR or immunohistochemistry. Hierarchical cluster analysis clearly distinguished between benign and malignant tissue and between squamous cell carcinomas and adenocarcinomas. The bronchial epithelium and adenocarcinomas could be divided into the two subgroups of smokers and non-smokers. By comparison of the gene expression profiles in the bronchial epithelium of non-smokers, smokers, and matched cancer tissues, it was possible to identify a signature of 23 differentially expressed genes, which might reflect early cigarette smoke-induced and cancer-relevant molecular lesions in the central bronchial epithelium of smokers. Ten of these genes are involved in xenobiotic metabolism and redox stress (eg AKR1B10, AKR1C1, and MT1K). One gene is a tumour suppressor gene (HLF); two genes act as oncogenes (FGFR3 and LMO3); two genes are involved in matrix degradation (MMP12 and PTHLH); three genes are related to cell differentiation (SPRR1B, RTN1, and MUC7); and five genes have not been well characterized to date. By comparison of the tobacco-exposed peripheral alveolar lung tissue of smokers with non-smokers and with adenocarcinomas from smokers, it was possible to identify a signature of 27 other differentially expressed genes. These genes are involved in the metabolism of xenobiotics (eg GPX2 and FMO3) and may represent cigarette smoke-induced, cancer-related molecular targets that may be utilized to identify smokers with increased risk for lung cancer.
Croute F, Beau B, Murat JC, et al.Expression of stress-related genes in a cadmium-resistant A549 human cell line.
J Toxicol Environ Health A. 2005; 68(9):703-18 [PubMed
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This study was designed to explain the basis for Cd-acquired tolerance of A549 cells cultured in the presence of Cd. Thirty-day exposure of cultured human pneumocytes (A549 cell line) to 10 microM Cd was previously found to induce an acquired resistance persisting over several weeks of culture. Moreover, these Cd-resistant cells (R-cells) were found to proliferate faster than controls. No difference was found between R-cells and control cells (S-cells) concerning the basal and Cd-induced level of metallothioneins expression. However, after exposure to Cd, cell glutathione levels were unchanged in R-cells while they were either increased (at 10 microM Cd) or decreased (at 25 microM Cd) in S-cells. cDNA array analysis showed that genes encoding for (GPx1) glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase were similarly expressed in R- and S-cells, whereas the gene of (GPx2) glutathione peroxidase was overexpressed in R-cells. Most genes encoding stress proteins were similarly expressed, except for HSP27 and GRP94 genes, which were respectively under- (ratio 0.5 +/- 0.1) and over- (1.8 +/- 0.5) expressed in R-cells. Acute exposure to Cd was found to trigger the upregulation of genes encoding the chaperone proteins HSP90A, HSP27, HSP40, GRP78, HSP72, and HO-1 in S-cells. In R-cells, only HO-1 and HSP72 were overexpressed but at a lower level. This suggests that the Cd-related adverse conditions, leading to protein misfolding, are lowered in R-cells. It is likely that the upregulation of GPx2 in R-cells leads to a higher antioxidant defense in these cells.
Chiu ST, Hsieh FJ, Chen SW, et al.Clinicopathologic correlation of up-regulated genes identified using cDNA microarray and real-time reverse transcription-PCR in human colorectal cancer.
Cancer Epidemiol Biomarkers Prev. 2005; 14(2):437-43 [PubMed
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PURPOSE: We hypothesize that changes in the transcription of up-regulated genes are biologically meaningful and may be linked to variations in tumor behavior and clinical features. This study aimed to find individual up-regulated genes responsible for clinicopathologic variations in human colorectal cancer.
EXPERIMENTAL DESIGN: Genes up-regulated concurrently in four microarray experiments were taken as candidate genes; 20 candidate genes were verified using real-time reverse transcription-PCR in these four experiments, along with 27 new samples. The presence or absence of up-regulation of these genes was correlated with 10 clinicopathologic variables from 31 patients. The mRNA transcript levels of these 20 candidate genes in the 31 paired samples were also correlated with each other to disclose any expression relationship.
RESULTS: Forty percent (8/20) of the candidate genes were verified by real-time reverse transcription-PCR to have a tumor/normal expression ratio > 2. Up-regulation of THY1 and PHLAD1 was associated with the presence of anemia in colon cancer patients (P = 0.036 and 0.009, respectively). Up-regulation of HNRPA1 was more significant in cancer growing in the right-sided colon than the left side (P = 0.027). Up-regulated GPX2 was related to a higher degree of tumor differentiation (P = 0.019). c-MYC was significantly over-expressed in specimens from male compared with female colon cancer patients (P = 0.012). GRO1 was significantly up-regulated in patients younger than 65 years old (P = 0.010) and was found to be frequently over-expressed when cancers were less invasive. In addition, we found that normalized transcript levels of HNRPA1 were tightly associated with that of c-MYC (r = 0.948).
CONCLUSIONS: Validation of microarray data using another independent laboratory approach is mandatory and statistical correlation between gene expression status and the patient's clinical features may reveal individual genes relevant to tumor behavior and clinicopathologic variations in human colorectal cancer.