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Chromosomal region maintenance 1 (CRM1) is associated with an adverse prognosis in glioma. We previously reported that CRM1 inhibition suppressed glioma cell proliferation both in vitro and in vivo. In this study, we investigated the role of CRM1 in the migration and invasion of glioma cells. S109, a novel reversible selective inhibitor of CRM1, was used to treat Human glioma U87 and U251 cells. Cell migration and invasion were evaluated by wound-healing and transwell invasion assays. The results showed that S109 significantly inhibited the migration and invasion of U87 and U251 cells. However, mutation of Cys528 in CRM1 abolished the inhibitory activity of S109 in glioma cells. Furthermore, we found that S109 treatment decreased the expression level and activity of MMP2 and reduced the level of phosphorylated STAT3 but not total STAT3. Therefore, the inhibition of migration and invasion induced by S109 may be associated with the downregulation of MMP2 activity and expression, and inactivation of the STAT3 signaling pathway. These results support our previous conclusion that inhibition of CRM1 is an attractive strategy for the treatment of glioma.
ABSTRACT
Chromosomal region maintenance 1 (CRM1) is associated with an adverse prognosis in glioma. We previously reported that CRM1 inhibition suppressed glioma cell proliferation both in vitro and in vivo. In this study, we investigated the role of CRM1 in the migration and invasion of glioma cells. S109, a novel reversible selective inhibitor of CRM1, was used to treat Human glioma U87 and U251 cells. Cell migration and invasion were evaluated by wound-healing and transwell invasion assays. The results showed that S109 significantly inhibited the migration and invasion of U87 and U251 cells. However, mutation of Cys528 in CRM1 abolished the inhibitory activity of S109 in glioma cells. Furthermore, we found that S109 treatment decreased the expression level and activity of MMP2 and reduced the level of phosphorylated STAT3 but not total STAT3. Therefore, the inhibition of migration and invasion induced by S109 may be associated with the downregulation of MMP2 activity and expression, and inactivation of the STAT3 signaling pathway. These results support our previous conclusion that inhibition of CRM1 is an attractive strategy for the treatment of glioma.
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Objective To explore the mechanisms and effects of adoptive immunotherapy with ovarian cancer vaccine modified by GM-CSF gene which was used after immunologic reconstitution during lymphopenia induced by chemotherapy.Methods Lymphopenia was induced by chemotherapy with cyclophosphamide.The immune reconstituted model was built in rats.The tumor vaccine draining lymph nodes were harvested after the ovarian cancer cells NUTU-19 modified by GM-CSF gene were injected.The effector T cells (T_E) were got after being stimulated and amplified.Enzyme-linked immunosorbent assay was used to detect the level of interleukin (IL)-2 and IL-4 secreted by T_E.Intracellular cytokine staining was used to determine frequency of tumor-specific T_E.Fluorescence-activated cell sorting (FACS) was used to detect the special cytotoxicity ofT_E killing target cells.The survival period of rats bearing pre-established abdominal ovariam carcinoma after being adoptively transferred byT_E.was observed.Results Compared with those in control group,the significant higher levels IL-2[(65.7±4.0) pg/ml]and lower levels IL-4 [(277±49) pg/ml]were observed in chemotherapy-immune recunstitution-vaccine immunization group.The amount of CD_4~+ T cells secreting interferon-γ (13.0±2.1)% were also significantly increased.The rate of the special cytotoxicity of killing T cells (86.5±1.1) % was markedly improved.The survival period of rats (110±16) days was increased in chemotherapy-immune reconstitution-vaccine immunization group.Conclusions The combined immunotherapy of chemotherapy-immune reconstitution-tumor vaccine immunotherapy may increase the frequency and function of specific tumor T_E.The specific cytotoxicity is increased and the weak reaction of T_E to tumor is improved,which showed that this therapy can enhance immune reaction.
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Objective: To study the relevance of expression of basic fibroblast growth factor (bFGF), fibroblast growth factor receptor-1 (FGFR-1) and carcinogenesis and progression of ovarian epithelial neoplasm. Methods: Ten cases of normal ovarian tissues and 75 cases of ovarian epithelial neoplasm tissues were detected by immunohistochemical methods: S-P for bFGF, FGFR-1, double immunohistochemistry Lab-SA for Ki-67 antigen and bFGF. Results: The expression level of bFGF, FGFR-1 in ovarian epithelium and ovarian epithelial neoplasm showed a step-wise increase in the following order: normal 〈benign 〈borderline 〈malignant; The expression level and intensity of bFGF and FGFR-1 were increased with the decrease of differentiation degree and increase of clinical stage in ovarian carcinoma; There was no statistical difference between the expression of bFGF, FGFR-1 in serous cystadenocarcinoma and that of mucinous cystadenocarcinoma; The expression of bFGF was correlated with that of FGFR-1 in neoplastic tissues; There were positive expression rates of bFGF and Ki-67 antigen in ovarian epithelial neoplasm. Conclusion: As an important proliferative factor, bFGF plays an important role in carcinogenisis and progression of ovarian epithelial neoplasm.
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0.05),but it was associated with the depth of invasive cervical and lymph node metastases(P
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Objective To study the apoptosis of ovarian carcinoma cell strain COC1 induced by arsenic trioxide (As_2O_3). Methods The effect of arsenic trioxide on the proliferation of ovarian carcinoma cell strains were examined, using Methyl thiazolyl tetrazolium(MTT) assay. Flow cytometry(FCM) was used to detect apoptosis percentage and phase distribution of cell cycles. After being exposed to As_2O_3 solution of different concentration, apoptosis morphologic features of COC1 were observed by TdT-mediated dUTP nick end labeling (TUNEL). Results Inhibition of As_2O_3 on the growth of COC1 was increasing with passing of time and increasing of concentration. After 48h of exposure to 1.5 ?mol/L As_2O_3, COC1 cell strains presented apoptosis morphologic change, and the number of apoptosis cells increased with the passage of time. After treatment with 3.0 ?mol/L or 1.5 ?mol/L As_2O_3, the percentage of COC1 cells in G_2/M phase declined, and the percentage of cells in G_1 phase increased with the passage of time. These results suggested that As_2O_3 inhibited the cellular proliferation of COC1 cells via arrest of cell cycle. Conclusion Arsenic trioxide can induce apoptosis of ovarian carcinoma cell strain COC1. It can block the cell cycle at the G_1 phase, which is one of the possible mechanisms of apoptosis induced by As_2O_3.
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Objective To study the expression and distribution of postsynaptic density protein-93(PSD-93) after spinal cord injury(SCI). Methods With improved Allen's method,acute rats SCI models were established.Real-time PCR and Western blotting were used to detect the changes of PSD-93 mRNA and protein expression after SCI.The changes of PSD-93 localization after injury were investigated by immunofluorescence double staining. Results The expression of PSD-93 mRNA had a gradually decrease trend after SCI.The minimal mRNA was present at 3days;whereas the protein levels up-regulated significantly and peaked at 1day after injury.Immunofluorescence double staining indictated that PSD-93 was highly expressed on the activated microglias and astrocytes except that it co-localized with nNOS in the impaired spinal cord.Conclusion The time course of PSD-93 and its mRNA is vary significantly after SCI,and colocalized with nNOS and activated glias.These results indicate that PSD-93 may participate in the following response after SCI.