ABSTRACT
The programmed cell death 4 (PDCD4) tumor-suppressor gene regulates cell apoptosis, protein translation, signal transduction, and induction of mediators of inflammation. However, the mechanism by which PDCD4 is down-regulated and regulates tumor growth remains elusive. In this study, we showed that PDCD4 is down-regulated in glioma cells and acts as a tumor suppressor. Based on the TCGA data, we confirmed that AKT2, but not AKT1 or AKT3, interacts with PDCD4, thus leading to the suppression of PDCD4 in glioma cells. Moreover, the analysis suggested that PDCD4 regulates the expression of IL-5, CCL-5, VEGF, and CXCL10 via the NF-kB pathway. Additionally, depletion of levels of PDCD4 promoted angiogenic activity of glioma cells via the VEGF-STAT3 pathway. When tumor cells over-expressing PDCD4 were injected into nude mice, the increased expression of PDCD4 blocked tumorigenesis and prolonged overall survival. Our study indicates the need to develop drugs that can modulate the expression of PDCD4 and test their efficacy in clinical trials.
ABSTRACT
Background and purpose:In recent studies, the Notch-1 gene has been found to play an important role in the development of human glioblastoma.Short interfering RNA(siRNA) was used to silence the Notch-1 gene and block its expression.The objective was to determine whether siRNA targeting Notch-1 would inhibit the formation and growth of tumors in nude mice that modeled human glioblastoma.Methods:The human glioblastoma cell line TJ905 were first cultured and transfected with Notch-1 siRNA or nonsense siRNA by OligofectamineTM.The TJ905 cells were divided into 3 groups:the Notch-1 siRNA transfected group, nonsense siRNA transfected group and the control group.Each group's cells were subcutaneously injected into 5 nude mice.The nude mice(males, 3-4 weeks old) were given subcutaneous injections of either 0.2 mL of transfected siRNA or with normal TJ905 cells suspended at a 1?107 cells/mL concentration in a DMEM medium without serum.One week later, when the tumors were palpable, they were directly injected with the Notch-1 siRNA complex, nonsense siRNA complex, or PBS every 4 days for 20 days.Tumor sizes were measured every 3 days and calculated by the formula:volume(mm3) =1/2 length?(width)2.After a 20-day follow-up period, the mice were exterminated.Immunohistochemistry was used to determine the expression of Notch-1 gene.Results:The final tumor volume was less in nude mice injected with Notch-1 siRNA(1 203?206) mm3 compared mice injected with the nonsense siRNA injection(2 241?401) mm3, P
