The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer.

BACKGROUND: The oncoprotein-18/stathmin 1 (STMN1), involved in cell progression and migration, is associated with clinical outcome in breast cancer. Here we aim to investigate its clinical significance in urinary bladder cancer and its possibilities as a therapeutic target. METHODS: Immunohistochemical analyses of STMN1 protein expression were performed in three patient cohorts: cohort I (n=115 Ta, n=115 T1, n=112 T2-4 stages), cohort II, based on randomised controlled trials (n=239 T1-T4), and cohort III of primary tumour/matched metastasis (n=90 T1-T4). The effects of STMN1 on cell proliferation and migration were evaluated in the urinary bladder cancer cell line, T24, by inhibiting STMN1-cellular expression using siRNA. RESULTS: In cohort I, high STMN1 expression correlated to shorter disease-specific survival hazard ratio (HR)=2.04 (95% confidence interval (CI) 1.13-3.68; P=0.02), elevated p53- (P<0.001) and Ki67-protein levels (P<0.001). The survival result was validated in cohort II: HR=1.76 (95% CI 1.04-2.99; P=0.03). In the metastatic bladder cancer material, 70% of the patients were STMN1-positive in both the primary tumour and matched metastases. In vitro, the growth and migration of the T24 cells were significantly reduced (P<0.01, P<0.0001, respectively), when transfecting the cells with STMN1-siRNA. CONCLUSIONS: STMN1 protein expression has prognostic significance but is primarily a potential treatment target in urinary bladder cancer.

Demethylation of methyl mercury in different brain sites of Macaca fascicularis monkeys during long-term subclinical methyl mercury exposure.

Total (T-Hg) and inorganic (I-Hg) mercury concentrations were determined in specific brain sites (cerebellum, occipital pole, pons, motor strip, frontal pole, temporal pole, thalamus, and pituitary) of female Macaca fascicularis monkeys exposed to daily peroral doses (50 micrograms Hg/kg body weight) of methyl mercury (MeHg) for 6, 12, or 18 months, or to continuous iv infusion of HgCl2 (200 micrograms Hg/kg body wt). In normal weight monkeys (2.4-4.1 kg body wt), the average concentration of MeHg (calculated as T-Hg minus I-Hg) was about the same in all brain sites, except the pituitary--3.0 micrograms Hg/g at 6 months, 4.2 micrograms/g at 12 months, and 4.3 micrograms Hg/g at 18 months. MeHg concentrations in the pituitary were about 50% of those in the other brain sites. In a group of monkeys that were kept unexposed for 6 months following 12 months of MeHg exposure, T 1/2 for MeHg was about 37 days in all brain sites, with the exception of the pituitary, where it was shorter. The concentration of I-Hg increased in all brain sites, but especially in the thalamus and pituitary, with the time of MeHg exposure. In most brain sites, I-Hg constituted about 9% of T-Hg at 6 and 12 months, and 12% of T-Hg at 18 months. In the pituitary, I-Hg increased from 20% of T-Hg at 6 months to 46% at 18 months. Elimination T 1/2 for I-Hg was extremely long, 230-540 days in most brain sites and considerably longer in the thalamus and pituitary. The concentration of I-Hg in the thalamus did not decrease during the clearance period (6 months), while I-Hg in the pituitary continued to increase in spite of no additional exposure. The MeHg exposed monkeys had several times higher I-Hg concentrations in the brain than monkeys exposed to HgCl2, indicating that I-Hg was formed by demethylation of MeHg in the brain, and not by brain uptake of I-Hg formed by demethylation elsewhere in the body. There were large variations in the relative concentration of I-Hg between individual monkeys, but not between brain sites (except thalamus and pituitary). Obese monkeys (5.0-6.1 kg body wt) exposed to MeHg had higher concentrations of both MeHg and I-Hg than normal weight monkeys in all brain sites, except in the pituitary.