Alterations of glutathione and GSTM1 mutations induce tumor metastasis and invasion via EMT pathway in breast cancer patients

Purpose: Alteration in the Glutathione (GSH) and Glutathione S-Transferase (GST) family lead to various disorders including breast cancer. However, the role of GSH and GSTM1 in the onset of breast cancer is still not fully elucidated. Objective: In the present study we observed considerable deficiency in the levels of glutathione and genetic mutation in the GSTM1 enzyme that influence susceptibility to breast cancer metastasis and invasion via EMT pathway. Methods: GSTM1 genotype was identified by multiplex polymerase chain reaction (PCR), RT-PCR and western blotting in breast cancer tissue samples and ANCT samples. The endogenous glutathione levels were determined by HPLC. The tumor metastasis, invasion and EMT biomarkers were determined by RT-PCR and western blot. The relationship between breast cancer, disease progression and histological status were estimated by one way analysis of variance and descriptive statistic. Data were analyzed using OriginPro 2015 statistics software (OriginLab, Northampton, USA). The correlation among different factors was assessed at 95% confidence intervals (CI) using the Mann-Whitney, Kruskal Wallis, and ANOVA test. P<0.05 was considered significant. Results: In present study genotyping analysis of GST investigated that genetic mutation in GSTM1 was detected in breast cancer tissue samples. Moreover, messenger RNA and protein analysis showed that GSTM1 was significant downregulated in tumor tissues (p=0.005, p=0.02) of breast cancer patients. Furthermore, significant reduction in the level of total glutathione level (GSHt P<0.05) was observed among correlation with patient ages, stages and histological grades, of breast cancer patients. Additionally, the result revealed that downregulation of GSTM1 promotes EMT pathway that leads to enhanced the expression of tumor proliferation, invasion and metastasis in breast cancer tissue samples compared with the ANCT samples (P<0.05). Conclusions The present findings suggest that GSTM1 genotype could be a potential biomarker that regulate EMT pathway associated with breast cancer prognosis.

Glutathione S-Transferase Genotype polymorphism and Primary Open-Angle Glaucoma in an Italian population

PurposeOxidative damage to the trabecular meshwork (TM) represents one of the pathogenic mechanisms leading to primary open angle glaucoma (POAG). Glutathione S-transferase mu 1 (GSTM1) may neutralizes reactive oxygen species protecting the TM. The present paper investigates the prevalence of GSTM1 null genotype in an Italian population, and its association with POAG treated either medically or surgically.MethodsIn a case-control study, the GSTM1 genotype was identified in POAGs and controls. The POAGs patients were divided in two groups: medical POAGs and surgical POAGS. Medical POAGs consisted of patients with a well-controlled intraocular pressure (IOP) by IOP-lowering medications and a stable visual field (VF). Patients with an uncontrolled IOP and a progressing VF that were submitted to incisional surgery formed the surgical POAGs’ group.ResultsWe enrolled 104 medical POAGs, 158 surgical POAGs and 263 Controls. No significative differences between the groups existed regarding age and gender (p=0.275 and p=0.950, respectively). All the enrolled subjects were Caucasian of Italian descents. The GSTM1 null genotype was identified in 57 (45.2%) medical POAGs, 91 (57.6%) surgical POAGs and, 119 (45.3%) controls (p=0.033). The association between medical POAG and GSTM1 null status was non-significant (OR= 1.44, 95% IC = 0.86 to 2.39) whereas the association was significant for surgical POAGs (OR= 2.01, 95% IC= 1.26 to 3.21)ConclusionsOur results showed an association between the GSTM1 null genotype and glaucoma that require surgery in an Italian population. GSTM1 null genotype detection may help to identify high-risk glaucoma patients that require a closer follow-up and a more aggressive treatments.

Influence of GSTM1, GSTT1 and GSTP1 xenobiotic metabolism genes polymorphisms on treatment efficiency in patients with chronic hepatitis C

Aim. To analyze the influence of GSTT1, GSTM1 and GSTP1 genes polymorphism on treatment effectiveness in patients with chronic hepatitis C in Odessa Region using different treatment protocols. Methods. Three groups of patients with chronic hepatitis C were included. Patients of the first group (n=33) were treated with peginterferon alfa-2a and ribavirin, of the second group (n=18) - with tilorone and ribavirin, of the third group (n=26) - with silybi mariani fructuum extract. GSTT1, GSTM1 genes polymorphisms, as well as A313G polymorphism of GSTP1 gene were determined. The treatment effect was assessed by changes of biochemical parameters and viral load. Results. Patients of the first group with AG + GG genotypes had higher rate of rapid and early virologic response (73.7 and 27.3% respectively, р=0.013). Level of alanine transaminase also normalized earlier, and was significantly lower after 12 weeks of treatment in patients with AG + GG genotypes (0.57±0.28 mmol/l×h) compared to patients with АА genotype (0.99±±0.77 mmol/l×h, р=0.033). There was no influence of GSTT1 and GSTM1 genes polymorphisms on the chance of rapid and early virologic response and alanine transaminase levels. No response was found only in 4 patients with GSTT1+/GSTM1+ genotype. Conclusion. GSTT1 and GSTM1 deletion genes polymorphisms did not influence the speed of virologic response in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. No virologic response in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin was only found in patients with GSTT1+/GSTM1+ genotype. AG + GG GSTP1 genotype was associated with more rapid alanine transaminase level normalization and rapid virologic response in patients treated with peginterferon alfa-2a and ribavirin. GSTT1+, GSTM1+ genotypes and АА genotype of GSTP1 gene are associated with better treatments results in patients treated with silybi mariani fructuum extract.

Gender-Dependent Effect of GSTM1 Genotype on Childhood Asthma Associated with Prenatal Tobacco Smoke Exposure

It remains unclear whether the GSTM1 genotype interacts with tobacco smoke exposure (TSE) in asthma development. This study aimed to investigate the interactions among GSTM1 genotype, gender, and prenatal TSE with regard to childhood asthma development. In a longitudinal birth cohort in Taiwan, 756 newborns completed a 6-year follow-up, and 591 children with DNA samples available for GSTM1 genotyping were included in the study,and the interactive influences of gender-GSTM1 genotyping-prenatal TSE on childhood asthma development were analyzed. Among these 591 children, 138 (23.4%) hadphysician-diagnosed asthmaat 6 years of age, and 347 (58.7%) werenull-GSTM1. Prenatal TSE significantly increased the prevalence of childhood asthma innull-GSTM1children relative to those withpositiveGSTM1. Further analysis showed that prenatal TSE significantly increased the risk of childhood asthma in girls withnull-GSTM1. Furthermore, among the children without prenatal TSE, girls withnull-GSTM1had a significantly lower risk of developing childhood asthma and a lower total IgE level at 6 years of age than those withpositiveGSTM1. This study demonstrates that the GSTM1 null genotype presents a protective effect against asthma development in girls, but the risk of asthma development increases significantly under prenatal TSE.