No abstract

In this paper, we report a study on the clinical relevance of prothymosin-α expression and its correlation with intratumoral Foxp3(+) and CD8(+) lymphocytes (Foxp3(+)TIL and CD8(+)TIL) in bladder cancer patients. We used immunohistochemical staining for prothymosin-α, Foxp3, and CD8 on 101 tumor specimens harvested by endoscopic resection. The results were correlated with clinicopathological variables and clinical outcome in bladder cancer patients, particularly in 73 patients with superficial disease, using the log-rank test and Cox proportional hazard model. Overall, of the tumors, 30 % were negative, 34 % showed nuclear, and 37 % showed cytoplasmic prothymosin-α expression. Foxp3(+)TILs were detected in 11 % of patients (nonnuclear vs. nuclear, p = 0.096). Patients with a history of urothelial carcinoma have a higher frequency of nonnuclear prothymosin-α expression than those without (p = 0.016, chi-square test). By univariate and multivariate analyses of cases with superficial disease, grade and stage were identified as independent predictors for recurrence-free survival (p = 0.016 and 0.016, respectively). Higher stage and nonnuclear prothymosin-α expression independently predict shorter progression-free survival (p = 0.006 and 0.043, respectively). The presence of Foxp3(+)TILs was significantly associated with disease progression by univariate analysis (p = 0.022), but not by multivariate analysis (p = 0.147). In vitro assays showed that J82 cells which express ectopically nuclear prothymosin-α exhibit higher growth rate and secrete less TGF-β1 than those with cytoplasmic expression or control cells. Altogether, prothymosin-α expression is a determinant of disease progression in superficial bladder cancer. Foxp3(+)TILs tend to be found more often in bladder cancer with nonnuclear prothymosin-α expression. Future study is required to unravel their interaction.

No abstract

Hypoxia-inducible factor-1α (HIF-1α) can control a transcriptional factor forkhead box P3 (Foxp3) protein expression in T lymphocyte differentiation through proteasome-mediated degradation. In this study, we unveil a reverse regulatory mechanism contributing to bladder cancer progression; Foxp3 expression attenuates HIF-1α degradation. We first demonstrated that Foxp3 expression positively correlates with the metastatic potential in T24 cells and can increase the expression of HIF-1α-target genes, such as vascular endothelial growth factor (VEGF) and glucose transporter (GLUT). Foxp3 protein can bind with HIF-1α, particularly under hypoxia. In vivo ubiquination assay demonstrated that Foxp3 can decrease HIF-1α degradation in a dose-dependent manner. Knocking-down of Foxp3 expression blocks in vivo tumor growth in mice and prolongs mice's survival, which is associated with von Willebrand factor expression. Thirty-three of 145 (22.8 %) bladder tumors exhibit Foxp3 expression. Foxp3 expression is an independent predictor for disease progression in superficial bladder cancer patients (p = 0.032), associated with less number of intratumoral CD8+ lymphocyte. The metaanalysis from 2 published datasets showed Foxp3 expression is positively associated with GLUT−4, −9, and VEGF-A, B-, D expression. This reverse post-translational regulation of HIF-1α protein by Foxp3 provides a new potential target for developing new therapeutic strategy for bladder cancer.

Abstract. although dickkopf-1 (dKK1) has been demonstrated to be associated with tumorigenesis in various types of human tumors, a correlation between dKK1 and urothelial carcinoma (uc) has not been reported. in the present study, the correlation between dKK1 expression and uc progression was investigated. Seventy-five UC patients were enrolled. the expression of dKK1 in serum and uc tissue was detected by EliSa, real-time pcr and Western blotting. prognostic significance was assessed by using Kaplan-Meier survival estimates and log-rank tests. the results showed that serum levels of DKK1 were significantly higher in the UC patients with muscle-invasive (p=0.0001) and high-grade tumors (p=0.00001) as compared to the controls. a high-serum dKK1 was also associated with poor disease-free survival in the uc patients (hazard ratio=2.44; 95% ci 1.10-5.40; p=0.028). Furthermore, dKK1 was also overexpressed in 93% (41/44) of the UC tissues. Therefore, the findings indicate that the expression of dKK1 is associated with uc progression. Introductionurothelial carcinoma (uc), also known as transitional cell carcinoma, is a malignant tumor arising from a transitional type of stratified epithelium, the urothelium, and affects the renal collecting system (1). it is the most common cancer of the urinary bladder and ureter (1) and the second leading cause of death among malignancies of the genitourinary tract system (2). in the case of bladder cancer, most diagnosed patients have non-muscle invasive disease with a high risk of recurrence (3). therefore, approaches for the determination of bladder cancer recurrence are important in medical care (4). at present, cystoscopic examination is recommended every 3-6 months for 3 years after surgical treatment (5). cystoscopy in combination with urinary cytology is the standard protocol for the detection and surveillance of bladder cancer.recently, dickkopf-1 (dKK1) was found to be associated with the development of several types of cancer, including Wilm's tumor, hepatoblastoma, hepatocellular carcinoma, colorectal cancer, lung and esophageal carcinomas, breast, cervical, endometrial and kidney cancers (6-10). dKK1 is a secreted protein that plays a crucial role in head formation during vertebrate development and specifically inhibits Wnt/β-catenin signaling (11). dKK1 binds to the lrp5/6 and Kremen proteins leading to lrp endocytosis, which prevents the formation of the Wnt-Frizzled-lrp5/6 receptor complex (12). Furthermore, the Wnt signaling pathway was found to be involved in the pathogenesis of uc (13)(14)(15)(16)(17)(18)(19). therefore, an association of dKK1 expression with uc is a reasonable speculation. To date, the significance of DKK1 activation in human uc is still not clear. in this study, the correlation between dKK1 expression and uc progression was investigated. Materials and methodsSubjects. Seventy-five UC patients who underwent surgery at the department of urology, chiayi christian hospital, were enrolled in the study. Seventy-five age-matched cancer-free volunteers ...