Edyta Reszka

Selenium and cancer: biomarkers of selenium status and molecular action of selenium supplements

BackgroundThe relationship between selenium and cancer involves many different aspects. These include the forms of selenium present in the diet and in the body, their functions and mechanisms of action, and methods employed in assessing an individual’s selenium nutritional status—both in general, and in epidemiological studies of the risk of cancer in relation to diet, as well as in connection with long-term trials for investigating the disease-preventive potential of selenium supplementation.Aim of the reviewTo review different aspects on selenium metabolism, the occurrence of different selenoproteins and their use as biomarkers of selenium status, the results of intervention trials of the cancer-preventive effects of selenium supplementation, the mechanisms of action involved, together with epidemiological findings on relations between the selenium status in the body and risk of cancer.Results and conclusionsThe rapid advance in the knowledge of different selenoproteins and their biological functions has opened up new possibilities for the understanding of the biological effects of selenium supplementation. A wide variety of effects of different forms and doses of selenium has been observed in a number of experimental systems, and it is at present difficult to pinpoint the mechanism that may explain the positive preventive effects of selenium supplementation observed in some human long-term trials. Moreover, additional such trials are needed to define the benefits and risks of different types and doses of selenium supplements which in the future may be implemented for public health reasons. Another necessary focus for future research is a better understanding of the mechanisms by which selenium interferes with the carcinogenesis process.

Genetic polymorphism of xenobiotic metabolising enzymes, diet and cancer susceptibility.

There is increasing evidence identifying the crucial role of numerous dietary components in modifying the process of carcinogenesis. The varied effects exerted by nutrient and non-nutrient dietary compounds on human health and cancer risk are one of the new challenges for nutritional sciences. In the present paper, an attempt is made to review the most recent epidemiological data on interactions between dietary factors and metabolic gene variants in terms of cancer risk. The majority of case-control studies indicate the significant relationship between cancer risk and polymorphic xenobiotic metabolising enzymes in relation to dietary components. The risk of colorectal cancer is associated not only with CYP2E1 high-activity alleles, but also GSTA1 low-activity alleles, among consumers of red or processed meat. Genetic polymorphisms of NAT1 and NAT2 may be also a breast-cancer susceptibility factor among postmenopausal women with a high intake of well-done meat. On the other hand, phytochemicals, especially isothiocyanates, have a protective effect against colorectal and lung cancers in individuals lacking GST genes. Moreover, polymorphism of GSTM1 seems to be involved in the dietary regulation of DNA damage. The European Prospective Investigation into Cancer and Nutrition study shows a significant inverse association between the polycyclic aromatic hydrocarbon-DNA adduct level and dietary antioxidants only among GSTM1-null individuals. However, the absence of a modulatory effect of polymorphic xenobiotic metabolising enzymes and diet on the development of cancer has been indicated by some epidemiological investigations. Studies of interactions between nutrients and genes may have great potential for exploring mechanisms, identifying susceptible populations/individuals and making practical use of study results to develop preventive strategies beneficial to human health.

Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

Background: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures. Methods: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status. Results: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07). Conclusion: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland. Impact: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association. Cancer Epidemiol Biomarkers Prev; 21(7); 1156–. ©2012 AACR.

Meta- and Pooled Analysis of GSTP1 Polymorphism and Lung Cancer: A HuGE-GSEC Review

Lung cancer is the most common cancer worldwide. Polymorphisms in genes associated with carcinogen metabolism may modulate risk of disease. Glutathione S-transferase pi (GSTP1) detoxifies polycyclic aromatic hydrocarbons found in cigarette smoke and is the most highly expressed glutathione S-transferase in lung tissue. A polymorphism in the GSTP1 gene, an A-to-G transition in exon 5 (Ile105Val, 313A --> 313G), results in lower activity among individuals who carry the valine allele. The authors present a meta- and a pooled analysis of case-control studies that examined the association between this polymorphism in GSTP1 and lung cancer risk (27 studies, 8,322 cases and 8,844 controls and 15 studies, 4,282 cases and 5,032 controls, respectively). Overall, the meta-analysis found no significant association between lung cancer risk and the GSTP1 exon 5 polymorphism. In the pooled analysis, there was an overall association (odds ratio = 1.11, 95% confidence interval: 1.03, 1.21) between lung cancer and carriage of the GSTP1 Val/Val or Ile/Val genotype compared with those carrying the Ile/Ile genotype. Increased risk varied by histologic type in Asians. There appears to be evidence for interaction between amount of smoking, the GSTP1 exon 5 polymorphism, and risk of lung cancer in whites.

Detection of infectious agents by polymerase chain reaction in human aortic wall

INTRODUCTION Several studies have been suggested that infectious agents may induce or progress the process of atherosclerosis in humans. In the present study, the samples of visually healthy human aortic wall were examined for the presence of Chlamydia pneumoniae, Mycoplasma pneumoniae, Helicobacter pylori, herpes simplex virus (HSV), and cytomegalovirus (CMV). METHODS Bacterial DNA of C. pneumoniae, M. pneumoniae, and H. pylori and viral DNA of HSV and CMV were analyzed by polymerase chain reaction. The specimens were obtained from 40 patients with atherosclerotic three-vessel stable coronary artery disease referred to surgical revascularization (coronary group) and 20 controls referred to aortic valve replacement (valve group). RESULTS C. pneumoniae was detected in 11 of 40 samples of aorta in coronary group (27.5%) and 5 of 20 in valve group (25%). M. pneumoniae was found in 6 of 40 (15%) and 5 of 20 (25%) samples, and CMV was found in 22 of 40 (55%) and 10 of 20 (50%) samples. The most frequent detected pathogens were H. pylori and HSV. H. pylori was found in 32 of 40 samples of aortic wall in coronary group (80%) and 17 of 20 samples in valve group (85%), whereas HSV was found in 27 of 40 (67.5%) and 17 of 20 (85%) aortic wall specimens. CONCLUSION Results demonstrate that C. pneumoniae, M. pneumoniae, H. pylori, CMV, and HSV can be detected in macroscopically healthy aortic wall of coronary and valve patients in similar frequency, which do not support hypothesis concerning the role of microorganisms in atherosclerosis etiology.

Night shift work characteristics and 6-sulfatoxymelatonin (MT6s) in rotating night shift nurses and midwives

Objectives Synthesis of melatonin follows a circadian cycle, with high melatonin levels during the night and low levels during the day. Light exposure at night has been hypothesised as one of potential mechanisms of breast carcinogenesis in the night shift workers through inhibition of melatonin synthesis. The aim of the study was to examine a number of determinants for night shift work in relation to 6-sulfatoxymelatonin (MT6s), primary melatonin metabolite. Methods The cross-sectional study included 354 nurses and midwives (aged 40–60 years) currently working on rotating night shifts and 370 working days only. Data from questionnaires and 1-week diaries were used to characterise current job and total occupational history. Associations between rotating night shift work characteristics and MT6s (creatinine adjusted) in spot morning urine were tested in multiple linear regression models. Results No significant differences were found for MT6s concentrations between women currently working on rotating night shifts and those working only day shifts (means 47.2 vs 45.7 ng/mg Cr, respectively). The adjusted means among rotating night shift nurses and midwives varied depending on the department of employment, from 35.1 ng/mg Cr in neonatology to 68.2 ng/mg Cr in the orthopaedics department. Women working eight or more night shifts per month had significantly lower MT6s levels than those having fewer night shifts per month (37.9 vs 47.4 ng/mg Cr, respectively). Total night shift work history was not associated with MT6s. Conclusions The results of this study indicate that working eight or more night shifts per month may disrupt the synthesis of melatonin.

Hypermethylation of p16 and DAPK promoter gene regions in patients with non-invasive urinary bladder cancer

Introduction The aim of the study was to examine the frequency of methylation status in promoter regions of p16 and DAPK genes in patients with non-invasive bladder cancer. Material and methods Forty-two patients (92.9% men, 73.8% smokers, 71.4% T1G1, 19.1% T1G2, 9.5% T1G3) and 36 healthy controls were studied. Isolation of genomic DNA from blood serum and methylation-specific PCR (MSP) were applied. Methylation status – methylated and unmethylated promoter regions of p16 and DAPK genes were analysed. Results Seventeen out of 42 patients (40.5%) had the methylated p16 gene, while methylation of the DAPK gene was seen in 27 of 42 cases (64.3%). In 12 patients (28.6%) both analysed genes were methylated. A statistically significant (p = 0.046) higher frequency of DAPK gene methylation (71.4%) was observed in patients with lower grade (G1) bladder cancer. Conclusions Detection of the aberrant hypermethylation of DAPK and p16 genes in blood DNA from non-invasive bladder cancer patients might offer an effective means for earlier auxiliary diagnosis of the malignancy.

Relevance of selenoprotein transcripts for selenium status in humans

The most commonly used methods for assessing the selenium (Se) status in humans involve analysis of Se concentration, selenoprotein activity, and concentration in the blood and its compartments. Recently, it has been suggested that the expression of selenoprotein mRNA in circulating blood leukocytes could differently reflect Se status, due to prioritization of specific selenoprotein synthesis in response to dietary Se supply. Whereas the Se levels required for optimization of selenoprotein P level and plasma glutathione peroxidise activity are well known, estimation of Se level that is required for maximal mRNA expression of selenoprotein in humans is the subject of current investigations. Studies on rats suggest that whole blood selenoprotein mRNA level can be used as the relevant molecular biomarker for assessing Se status, and suboptimal Se intake may be sufficient to achieve effective expression. Human studies, however, did not confirm this hypothesis. According to studies on rodents and humans discussed in this review, it appears that suboptimal Se intake may be sufficient to satisfy molecular requirements of Se and it is lower than current recommended dietary intake in humans. The use of selenoprotein transcripts as a molecular biomarker of Se status requires further studies on a large group of healthy individuals with different baseline Se, including data regarding genetic polymorphism of selenoproteins and data regarding potential modifiers of Se metabolism.

Level of selenoprotein transcripts in peripheral leukocytes of patients with bladder cancer and healthy individuals.

Abstract Background: Low concentrations of selenium (Se) in humans have been associated with risk of cancer. Selenoprotein mRNAs can potentially be regulated by Se status. Methods: Se status, GPx1 Pro198Leu and Sep15 1125G/A genetic polymorphism and human (h)GPx1, hGPx3, hSep15 and hSeP1 transcript levels in peripheral leukocytes of 33 males with bladder cancer and 47 healthy male controls were analysed. Results: All the subjects expressed detectable selenoprotein mRNA concentrations in leukocytes. Significantly lower expression of hGPx1, hGPx3, hSep15 and hSeP1 in leukocytes of bladder cancer patients compared to controls was observed. hGPx1, hGPx3 and hSep15 expression was significantly lower in non-smokers in the control group compared with smokers in the control group. A positive relationship between expression of all studied genes was also observed in non-smoking controls. Expression of hGPx3 and hSep15 gradually increased with tumour grade in patients with cancer. We did not find any association between selenoprotein mRNA levels, Se status and selenoprotein genetic polymorphism. Conclusions: This study showed significant down-regulation of hGPx1, hGPx3, hSep15 and hSeP1 mRNA levels in leukocytes of patients with bladder cancer compared to controls. Selenoprotein transcript levels in circulating leukocytes of patients with bladder cancer and controls revealed no potential impact of Se status on selenoprotein expression. Clin Chem Lab Med 2009;47:1125–32.

Matrix metalloproteinases and genetic mouse models in cancer research: a mini-review

Carcinogenesis is a multistep and also a multifactorial process that involves agents like genetic and environmental factors. Matrix metalloproteinases (MMPs) are major proteolytic enzymes which are involved in cancer cell migration, invasion, and metastasis. Genetic variations in genes encoding the MMPs were shown in human studies to influence cancer risk and phenotypic features of a tumor. The complex role of MMPs seems to be important in the mechanism of carcinogenesis, but it is not well recognized. Rodent studies concentrated particularly on the better understanding of the biological functions of the MMPs and their impact on the pathological process, also through the modification of Mmp genes. This review presents current knowledge and the existing evidence on the importance of selected MMPs in genetic mouse models of cancer and human genetic association studies. Further, this work can be useful for scientists studying the role of the genetic impact of MMPs in carcinogenesis.