Higher Trx1 Research Articles

Thioredoxin 1 (Trx1) is associated with poor prognosis in clear cell renal cell carcinoma (ccRCC): an example for the crucial role of redox signaling in ccRCC

PurposeThioredoxins are major regulatory proteins of oxidative signaling. Trx1 is the most prominent thioredoxin and, therefore, the current study sought to evaluate the prognostic role of Trx1 in ccRCC.Methods and patientsA tissue micro-array (TMA) study was carried out to evaluate the association of Trx1 with clinicopathological features and survival outcome. Data from the Cancer Genome Atlas (TCGA) were evaluated for the association of characteristics in the Trx1 gene with clinicopathological features and survival outcome.ResultsIn the TMA, patients with ccRCC that had high Trx1 levels had lower T stages (p < 0.001), less often distant metastases (p = 0.018), lower nuclear grades (p < 0.001), and less often tumor necrosis (p = 0.037) or sarcomatoid features (p = 0.008). Patients with a combined score of ≥ 10 had better DSS than patients with a low combined score of < 10 (HR 95% CI 0.62 (0.39–0.98)). Interestingly, the survival outcome is compartment specific: ccRCC patients whose tumors had exclusively Trx1 expression in the cytoplasm had the worst survival outcome (HR 3.1; 95% CI 1.2–8.0). Genomic data from the TCGA demonstrated that patients with ccRCCs that had Trx1 losses had more advanced clinicopathological features and worse survival outcome in disease specific (p < 0.001), overall (p = 0.001), and progression free survival (p = 0.001) when compared to patients with ccRCCs without copy number variations (CNV) or gains.ConclusionThe current study suggests a possible role of Trx1 in the tumor biology of ccRCC and thus, the current study strongly advises in depth investigations of redox signaling pathways in ccRCC.

Increased Thioredoxin-1 Expression Promotes Cancer Progression and Predicts Poor Prognosis in Patients with Gastric Cancer

Background Thioredoxin-1 (Trx-1) is a small redox protein, which plays an important role in many biological processes. Although increased expression of Trx-1 in various solid tumors has been reported, the prognostic significance and function of Trx-1 in human gastric cancer (GC) are still unclear. Here, we investigated the clinical and prognostic significance of Trx-1 expression and the function and mechanism of Trx-1 in human GC. Methods We analyzed Trx-1 mRNA expression from the GEO database and Trx-1 protein expression in 144 GC tissues using immunohistochemistry. Effects of Trx-1 on GC cell were assessed in vitro and in vivo through Trx-1 knockdown or overexpression. The antitumor effects of the Trx-1 inhibitor, PX-12, on GC cells were investigated. PTEN and p-AKT expressions were evaluated by Western blotting. Results Increased Trx-1 expression was found in GC tissues and associated with poor prognosis and aggressive clinicopathological characteristics in patients with GC. High Trx-1 expression predicted poor prognosis, and its expression was an independent prognostic factor for overall survival of GC patients. Knockdown of Trx-1 expression inhibited GC cell growth, migration, and invasion in vitro and tumor growth and lung metastasis in vivo. Conversely, overexpression of Trx-1 promoted GC cell growth, migration, and invasion. We also found that PX-12 inhibited GC cell growth, migration, and invasion. Overexpression of Trx-1 caused a decrease in PTEN and increase in p-AKT levels whereas silencing Trx-1 caused an increase in PTEN and decrease in p-AKT levels in GC cells. Inhibition of AKT signaling pathway by MK2206 also inhibited GC cell growth, migration, and invasion. Conclusion Our results indicate that Trx-1 may be a promising prognostic indicator and therapeutic target for GC patients.

Cellular stress and redox activity proteins are involved in gastric carcinogenesis associated with Helicobacter pylori infection expressing high levels of thioredoxin-1.

Helicobacter pylori infection is related to the development of gastric diseases. Our previous studies showed that high thioredoxin-1 (Trx1) expression in H. pylori can promote gastric carcinogenesis. To explore the underlying molecular mechanisms, we performed an isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic analysis of stomach tissues from Mongolian gerbil infected with H. pylori expressing high and low Trx1. Differences in the profiles of the expressed proteins were analyzed by bioinformatics and verified using Western blot analysis. We found three candidate proteins, 14-3-3α/β, glutathione-S-transferase (GST), and heat shock protein 70 (HSP70), in high Trx1 tissues compared with low Trx1 tissues and concluded that cellular stress and redox activity-related proteins were involved in the pathogenesis of gastric cancer associated with H. pylori Trx1.

High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab.

The humanized non-depleting anti-CD4 monoclonal antibody Tregalizumab (BT-061) is able to selectively activate the suppressive function of regulatory T cells and has been investigated up to phase IIb in clinical trials in patients suffering from rheumatoid arthritis (RA). A pharmacokinetic–pharmacodynamic model based on clinical data from RA and healthy volunteers, which used the cell surface CD4 downmodulation as marker of activity, confirmed a stronger effect in healthy volunteers compared with RA patients. We tried to understand this phenomenon and evaluated the influence of the small oxidoreductase thioredoxin-1 (Trx1). To counteract oxidative stress that is strongly associated with RA pathophysiology, the organism employs Trx1. Therefore, increased expression and secretion of Trx1 is found in the synovial fluid and plasma of RA patients. Moreover, the binding site of Tregalizumab is in close proximity to a disulphide bond in domain 2 (D2) of CD4, which is a known target for a reduction by oxidoreductase Trx1. With the experiments reported herein, we demonstrated that specific reduction of the D2 disulphide bond by Trx1 led to diminished binding of Tregalizumab to recombinant human soluble CD4 and membrane-bound CD4 on T cells. Moreover, we showed that this caused changes in the Tregalizumab-induced CD4 signalling pathway via the lymphocyte-specific protein tyrosine kinase p56Lck and CD4 downmodulation. In summary, we provide evidence that high Trx1 levels in RA patients compared with healthy subjects are a potential reason for diminished binding of Tregalizumab to CD4-positive T cells and offer an explanation for the observed decreased CD4 downmodulation in RA patients in comparison to healthy subjects.

The Progress in Helicobacter Pylori High Risk Pathogenic Marke

It has been widely accepted that Helicobacter pylori was closed related with tumorigenesis of gastric cancer, but the pathogenic factor of this bacteria as well as the intrinsic mechanism are still unclear. We analyzed the proteomics of Helicobacter pylori strains isolated from both gastritis and gastric cancer and discovered several differential proteins. Among these proteins the Thioredoxin-1 (Trx-1) was considered most significant. Trx-1 protein has an anti-oxidative function and might increase cellular proliferation and anti-apoptosis. It helped to protect Helicobacter pylori from the oxidative reaction from the host so as lead to the long term colonization. We carried out a series of researches on this protein. The results revealed that Trx-1 was highly expressed in Helicobacter pylori isolated from cancer patients compared with the bacteria from gastritis patients. In cell culture study, up-regulation of Trx-1 expression in GES-1 and BCG823 cell lines might increase cell growth and promote cells into S phase. What’s more, infected with Helicobacter pylori that express high level Trx-1 might induced cell apoptosis, decreased the expression of cyclin D1 and upregulated p21 in GES-1 cell line, while increase cell proliferation, and upregulate cyclin D1 in BCG823 cell line, indicating an oncogenic effects. We further infected Mongolian gerbils by Helicobacter pylori with high level Trx-1. The results showed long term infection lead to serious pathologic change of the stomach mucosa and finally adenocarcinoma occurred. In conclusion, Helicobacter pylori Trx-1 may play an important role in the development of stomach adenocarcinoma and can be considered as pathogenic marker. Future studies are still necessary for the specific process of Trx-1 protein on gastric mucosal after H. pylori infection, the relationship between clinical TNM stages and Hp Trx-1 level, as well as the downstream signal pathways that are involved in the carcinogenic process.

Helicobacter pylori with high thioredoxin-1 expression promotes stomach carcinogenesis in Mongolian gerbils

Previous studies by this group have shown that Helicobacter pylori with high thioredoxin-1 (Trx1) expression might be involved in stomach carcinogenesis in vitro. To study histopathological changes of the stomach mucosa in vivo, a Mongolian gerbil model infected with H.pylori with high Trx1 expression was established. Healthy, male Mongolian gerbils (n=75) were randomly divided into 3 groups: controls (n=15), which were not infected with H.pylori, high Trx1 (n=30) which were infected with H.pylori with high Trx1 expression and low Trx1 (n=30) which were infected with low Trx1 expression H.pylori. The animals were sacrificed at 4, 20, 34, 48, 70 and 90 weeks after inoculation. The Mongolian gerbil model of H.pylori infection was successfully established. Three animals died during the study, leaving 72 animals (controls, n=14; low Trx1, n=29; high Trx1, n=29) examined on schedule. Histopathological analysis of the stomach mucosa showed gradually increased aggravation over time in the high and low Trx1 groups. Compared with control and low Trx1, the histopathological changes were more serious in the high Trx1 group. At 90 weeks, no abnormal changes were found in the controls, but 62.5% of the high Trx1 group and 33.3% of the low Trx1 showed adenocarcinomas. The H.pylori Trx1 level in gastric cancer tissue was significantly higher than that from gastritis tissue. Within gastric cancer cells, high Trx1 expression in H.pylori significantly upregulated cyclin D1. High Trx1 expression in H.pylori promoted stomach carcinogenesis. More studies are needed to confirm this finding.

The involvement of Helicobacter pylori thioredoxin-1 in gastric carcinogenesis

Helicobacter pylori infection is related to the development of gastric diseases. Various virulence factors are responsible for the pathogenic mechanisms of H. pylori infection. Our previous studies using two-dimensional gel electrophoresis showed that H. pylori thioredoxin-1 (Trx1) is overexpressed in gastric carcinomas. Here, we examined whether H. pylori Trx1 is a novel virulence factor associated with gastric tumorigenesis. We found that Trx1 expression in H. pylori isolated from gastric cancer tissues was significantly higher than that from tissues exhibiting gastritis. In the gastric epithelial cell line GES-1, infection of H. pylori with high Trx1 expression significantly induced cell apoptosis, decreased the expression of cyclin D1 and upregulated p21. However, in the gastric cancer cell line BGC823, high Trx1 expression in H. pylori significantly increased cell proliferation, and upregulated cyclin D1. The effects on cell lines were confirmed using the H. pylori Trx1-knockout mutant strain. Our observations indicate that high Trx1 expression in H. pylori is associated with gastric carcinogenesis. In H. pylori, Trx1 likely participates in the pathogenesis of gastric cancer and H. pylori expressing high levels of Trx1 would be expected to be highly pathogenic in gastric diseases in China.

6506 ORAL A prognostic model based on BRCA1 mRNA expression: a new determinant of outcome in early non-small-cell lung cancer (NSCLC)

Previous studies by this group have shown that Helicobacter pylori with high thioredoxin-1 (Trx1) expression might be involved in stomach carcinogenesis in vitro. To study histopathological changes of the stomach mucosa in vivo, a Mongolian gerbil model infected with H. pylori with high Trx1 expression was established.Healthy, male Mongolian gerbils (n = 75) were randomly divided into 3 groups: controls (n = 15), which were not infected with H. pylori, high Trx1 (n = 30) which were infected with H. pylori with high Trx1 expression and low Trx1 (n = 30) which were infected with low Trx1 expression H. pylori. The animals were sacrificed at 4, 20, 34, 48, 70 and 90 weeks after inoculation.The Mongolian gerbil model of H. pylori infection was successfully established. Three animals died during the study, leaving 72 animals (controls, n = 14; low Trx1, n = 29; high Trx1, n = 29) examined on schedule. Histopathological analysis of the stomach mucosa showed gradually increased aggravation over time in the high and low Trx1 groups. Compared with control and low Trx1, the histopathological changes were more serious in the high Trx1 group. At 90 weeks, no abnormal changes were found in the controls, but 62.5% of the high Trx1 group and 33.3% of the low Trx1 showed adenocarcinomas. The H. pylori Trx1 level in gastric cancer tissue was significantly higher than that from gastritis tissue. Within gastric cancer cells, high Trx1 expression in H. pylori significantly upregulated cyclin D1.High Trx1 expression in H. pylori promoted stomach carcinogenesis. More studies are needed to confirm this finding.

Nuclear thioredoxin-1 is required to suppress cisplatin-mediated apoptosis of MCF-7 cells

Different cell line with increased thioredoxin-1 (Trx-1) showed a decreased or increased sensitivity to cell killing by cisplatin. Recently, several studies found that the subcellular localization of Trx-1 is closely associated with its functions. In this study, we explored the association of the nuclear Trx-1 with the cisplatin-mediated apoptosis of breast cancer cells MCF-7. Firstly, we found that higher total Trx-1 accompanied by no change of nuclear Trx-1 can not influence apoptosis induced by cisplatin in MCF-7 cells transferred with Trx-1 cDNA. Secondly, higher nuclear Trx-1 accompanied by no change of total Trx-1 can protect cells from apoptosis induced by cisplatin. Thirdly, high nuclear Trx-1 involves in the cisplatin-resistance in cisplatin-resistive cells. Meanwhile, we found that the mRNA level of p53 is closely correlated with the level of nuclear Trx-1. In summary, we concluded that the nuclear Trx-1 is required to resist apoptosis of MCF-7 cells induced by cisplatin, probably through up-regulating the anti-apoptotic gene, p53.