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Assessment of Oxidative Stress Genes SOD2 and SOD3 Polymorphisms Role in Human Colorectal Cancer.

ABSTRACT: PURPOSE:The aim of this study was to ascertain the oxidative stress genes SOD2 and SOD3 polymorphisms in patients with colorectal cancer and to assess the possible involvement of these polymorphisms that might increase the risk for patients to develop malignant intestinal tumors. MATERIAL AND METHODS:A total number of 306 subjects were divided into two groups (109 colorectal cancer patients as the study group and 197 normal healthy individuals as the control group).We genotyped two polymorphisms, SOD2 - 201A>G (rs4880) and SOD3 - 896C>G (rs1799895), by allelic discrimination, with TaqMan RT-PCR specific probes. RESULTS:No significant differences were found with either of the polymorphisms when comparing the association between them and an increased risk of developing colorectal tumors. CONCLUSION:In Romanian population, the risk of developing colorectal cancer is not increased by SOD2 and SOD3 polymorphisms.

SUBMITTER: Marginean C

PROVIDER: S-EPMC6269622 | biostudies-literature | 2016 Oct-Dec

REPOSITORIES: biostudies-literature

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Assessment of Oxidative Stress Genes SOD2 and SOD3 Polymorphisms Role in Human Colorectal Cancer.

Marginean C C Streata I I Ioana M M Marginean O M OM Padureanu V V Saftoiu A A Petrescu I I Tudorache S S Tica O S OS Petrescu F F

Current health sciences journal 20160228 4

<h4>Purpose</h4>The aim of this study was to ascertain the oxidative stress genes SOD2 and SOD3 polymorphisms in patients with colorectal cancer and to assess the possible involvement of these polymorphisms that might increase the risk for patients to develop malignant intestinal tumors.<h4>Material and methods</h4>A total number of 306 subjects were divided into two groups (109 colorectal cancer patients as the study group and 197 normal healthy individuals as the control group).We genotyped tw ...[more]

PMID: 30581589

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Project description:RATIONALE:Clinical studies have shown that Sirt3 (Sirtuin 3) expression declines by 40% by 65 years of age paralleling the increased incidence of hypertension and metabolic conditions further inactivate Sirt3 because of increased NADH (nicotinamide adenine dinucleotide, reduced form) and acetyl-CoA levels. Sirt3 impairment reduces the activity of a key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2) because of hyperacetylation. OBJECTIVE:In this study, we examined whether the loss of Sirt3 activity increases vascular oxidative stress because of SOD2 hyperacetylation and promotes endothelial dysfunction and hypertension. METHODS AND RESULTS:Hypertension was markedly increased in Sirt3-knockout (Sirt3-/-) and SOD2-depleted (SOD2+/-) mice in response to low dose of angiotensin II (0.3 mg/kg per day) compared with wild-type C57Bl/6J mice. Sirt3 depletion increased SOD2 acetylation, elevated mitochondrial O2·?-, and diminished endothelial nitric oxide. Angiotensin II-induced hypertension was associated with Sirt3 S-glutathionylation, acetylation of vascular SOD2, and reduced SOD2 activity. Scavenging of mitochondrial H2O2 in mCAT mice expressing mitochondria-targeted catalase prevented Sirt3 and SOD2 impairment and attenuated hypertension. Treatment of mice after onset of hypertension with a mitochondria-targeted H2O2 scavenger, mitochondria-targeted hydrogen peroxide scavenger ebselen, reduced Sirt3 S-glutathionylation, diminished SOD2 acetylation, and reduced blood pressure in wild-type but not in Sirt3-/- mice, whereas an SOD2 mimetic, (2-[2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino]-2-oxoethyl) triphenylphosphonium (mitoTEMPO), reduced blood pressure and improved vasorelaxation both in Sirt3-/- and wild-type mice. SOD2 acetylation had an inverse correlation with SOD2 activity and a direct correlation with the severity of hypertension. Analysis of human subjects with essential hypertension showed 2.6-fold increase in SOD2 acetylation and 1.4-fold decrease in Sirt3 levels, whereas SOD2 expression was not affected. CONCLUSIONS:Our data suggest that diminished Sirt3 expression and redox inactivation of Sirt3 lead to SOD2 inactivation and contributes to the pathogenesis of hypertension.

Project description:Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by an excessive production of pro-inflammatory cytokines resulting in chronic inflammation and genomic instability. Besides the driver mutations in JAK2, MPL, and CALR genes, the deregulation of miRNA expression may also contribute to the pathogenesis of PMF. To this end, we recently reported the upregulation of miR-382-5p in PMF CD34+ cells. In order to unveil the mechanistic details of the role of miR-382-5p in pathogenesis of PMF, we performed gene expression profiling of CD34+ cells overexpressing miR-382-5p. Among the downregulated genes, we identified superoxide dismutase 2 (SOD2), which is a predicted target of miR-382-5p. Subsequently, we confirmed miR-382-5p/SOD2 interaction by luciferase assay and we showed that miR-382-5p overexpression in CD34+ cells causes the decrease in SOD2 activity leading to reactive oxygen species (ROS) accumulation and oxidative DNA damage. In addition, our data indicate that inhibition of miR-382-5p in PMF CD34+ cells restores SOD2 function, induces ROS disposal, and reduces DNA oxidation. Since the pro-inflammatory cytokine transforming growth factor-β1 (TGF-β1) is a key player in PMF pathogenesis, we further investigated the effect of TGF-β1 on ROS and miR-382-5p levels. Our data showed that TGF-β1 treatment enhances miR-382-5p expression and reduces SOD2 activity leading to ROS accumulation. Finally, inhibition of TGF-β1 signaling in PMF CD34+ cells by galunisertib significantly reduced miR-382-5p expression and ROS accumulation and restored SOD2 activity. As a whole, this study reports that TGF-β1/miR-382-5p/SOD2 axis deregulation in PMF cells is linked to ROS overproduction that may contribute to enhanced oxidative stress and inflammation. Our results suggest that galunisertib may represent an effective drug reducing abnormal oxidative stress induced by TGF-β1 in PMF patients. DATABASE LINKING: GEO: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103464.

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Assessment of Oxidative Stress Genes SOD2 and SOD3 Polymorphisms Role in Human Colorectal Cancer.

Publications

Assessment of Oxidative Stress Genes SOD2 and SOD3 Polymorphisms Role in Human Colorectal Cancer.

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