[en] Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments. Proteasome inhibitors (PIs) and TNFα-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM. Treatment with 0.5-1 μM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10–20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells. The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs

[en] 

Purpose

Autoantibody to 14-3-3 zeta was identified in gastric cancer (GC) by serological proteome analysis (SERPA) in our previous study. We comprehensively evaluated its ability to detect GC, determined its association with clinical characteristics, and explored its temporal change in GC patients before and after gastrectomy resection in this study.

Methods

Anti-14-3-3 zeta antibody was examined by immunoassay in sera from 465 GC patients and 465 normal individuals, and also in 69 serial sera from 26 GC patients before and after resection.

Results

The frequency of anti-14-3-3 zeta were significantly higher in GC group than in control group, with AUC of 0.627. The appearance of anti-14-3-3 zeta showed no difference in different tumor stage, tumor size, tumor differentiation, and lymphatic metastasis, but was higher in GC patients with family tumor history than without family tumor history. When anti-14-3-3 zeta was combined with clinical markers (CEA, CA199 and CA724), the sensitivity increased to 52.7%. In the follow-up analysis, the titer of anti-14-3-3 zeta was higher in post-resection sera than pre-resection sera, and no difference was observed in CEA, CA199 and CA724. Anti-14-3-3 zeta showed an increase from negative status to positive status in six patients after resection, while other three clinical markers presented different change in GC patients after resection.

Conclusions

Autoantibody against 14-3-3 zeta could be a potential diagnostic biomarker and improve the sensitivity of CEA, CA199 and CA724 in diagnosis of GC. Further largescale studies will be needed to validate its performance in GC patients after resection.

[en] Angiogenesis and vessel remodeling are fundamental to the pathogenesis of a number of diseases caused by environmental arsenic exposure, including tumorigenesis and cardiovascular diseases. Arsenic (AsIII) has been shown to stimulate angiogenesis and vascular remodeling in vivo. However, the exact molecular mechanisms accounting for arsenic-induced angiogenesis are not clear. The present study investigates the role of heme oxygenase-1 (HO-1) in sodium arsenite-mediated angiogenesis in vitro. Transwell assay, three-dimensional Matrigel assay, RT-PCR, ELISA and immunoblotting were used to determine cell migration, vascular tube formation, mRNA and protein expression. Chromatin immunoprecipitation and luciferase assay were applied to examine the DNA binding with protein and HO-1 transcriptional activity. Here, we report that low concentrations of arsenite (0.1-1 μM) stimulated cell migration and vascular tube formation in human microvascular endothelial cells (HMVEC). Arsenite induced HO-1 mRNA and protein expression. Knock down of HO-1 expression decreased arsenite-induced VEGF expression, cell migration, and tube formation. We showed that arsenite promoted dissociation of Bach1 (a transcriptional repressor) from the HO-1 enhancers and increased Nrf2 binding to these elements. Site directed mutagenesis assay identified that Bach1 cysteine residues 557 and 574 were essential for the induction of HO-1 gene in response to arsenite. These findings demonstrate a role for HO-1 in arsenite-mediated angiogenesis in vitro.