ABSTRACT
We investigated whether inhibiting phosphorylated p70S6K (p-p70S6K) suppresses the proliferation and growth of noninvasive low-grade urothelial carcinoma (LG-URCa) in vitroand whether p-p70S6K can serve as a predictive biomarker for the recurrence of noninvasive LG-URCa of the bladder in patients. We constructed a tissue microarray (TMA) for 95 LG-URCa and 35 benign urothelium samples and performed immunohistochemical staining for p-p70S6K and p-4E-BP1. A Cox regression model was used to investigate the predictive factors for recurrence of LG-URCa. We investigated the dose-dependent antiproliferative effect of rapamycin, its antiproliferative effect and the growth-inhibition effect of p70S6K siRNA transfection in RT4 and 253J cell lines. The pT1 staged group (P < 0.05; hazard ratio (HR), 2.415) and the high p-p70S6K staining group (P < 0.05; HR, 2.249) were independent factors for predicting recurrence. Rapamycin inhibited RT4 and 253J cell proliferation in a dose-dependent manner (r = -0.850, P< 0.001 in RT4 cells; r = -0.835, P< 0.001 in 253J cells). RT4 and 253J cell proliferation and growth were inhibited by the transfection of p70S6K siRNA and rapamycin, respectively (P < 0.05). Transfection of p70S6K siRNA resulted in inhibitory effects on cell proliferation and growth that were similar to those of rapamycin. Our results suggest that inhibiting p70S6K phosphorylation is important to prevent recurrence and that p70S6K phosphorylation can be used as a molecular biomarker to predict recurrence of certain LG-URCa of the bladder.
Subject(s)
Carcinoma, Transitional Cell/metabolism , Neoplasm Recurrence, Local/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Urinary Bladder Neoplasms/metabolism , Urothelium/metabolism , Adult , Aged , Aged, 80 and over , Carcinoma, Transitional Cell/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Phosphorylation/drug effects , Signal Transduction/drug effects , Sirolimus/pharmacology , Urinary Bladder/drug effects , Urinary Bladder/metabolism , Urinary Bladder/pathology , Urinary Bladder Neoplasms/pathology , Urothelium/drug effects , Urothelium/pathologyABSTRACT
PURPOSE: To analyze the independent effect of metabolic syndrome (MS) on nephrolithiasis (NL) despite differences in gender compared with the known lithogenic factors. MATERIALS AND METHODS: From 1995 to 2009, 40,687 Koreans were enrolled in the study and observed for the development of NL at a health promotion center. The examination included anthropometric and biochemical measurements as well as kidney ultrasonography. A student's t-test or chi-square test was used to characterize the participants and a standard Cox proportional hazards model was used to calculate the adjusted odds ratio of lithogenic risk factors in the NL model. RESULTS: The mean age of the study cohort was 44.9 years (range, 13-100 years), and 22,540 (55.4%) of the cohort was male. The incidence of NL was 1.5% (609 participants), with males exhibiting a higher incidence than females (1.9% vs 1.0%, p<0.01). Among the total cohort, MS as well as each trait of MS were risk factors for NL. In males, high body mass index (BMI), high blood pressure, and abnormal glucose metabolism were significant lithogenic factors, whereas in females, lithogenic factors included only high BMI and abnormal glucose metabolism. CONCLUSIONS: MS is a significant lithogenic factor compared with other lithogenic factors. There was a correlated change in the prevalence of MS and NL and MS traits in Korea.
