Abstract The serine protease inhibitor (SERPIN) B1 is expressed in numerous human tumors, but little is known regarding its role in the pathophysiology of glioma. In this paper, we report that ...SERPINB1 expression was down-regulated in high-grade human glioma tissue samples and glioblastoma cell lines. To investigate the role of SERPINB1 in glioma migration and invasion, we generated human glioma cell lines in which SERPINB1 was either overexpressed or depleted. Overexpression of SERPINB1 suppressed, while elimination of SERPINB1 promoted, the migration and invasion of glioma cells. SERPINB1 inhibited glioma migration and invasion probably by dampening the expression of matrix metalloproteinase-2 (MMP-2). Molecular data showed that the effect of SERPINB1 in glioma cells might be mediated via sustained inactivation of the phosphorylation of focal adhesion kinase (FAK) involved in the downregulation of the expressions of MMP-2. In a multivariate analysis, high SERPINB1 expression was showed to be associated with good prognosis in glioma. In conclusion, our data suggest that SERPINB1 negatively regulates glioma cell migration and invasion probably by abrogating the expression of MMP-2 and the activation of FAK. We suggest that SERPINB1 may offer the application in clinical medicine.
Cell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). In particular, the expression levels of integrin β1 and its ...sub-cellular distribution (internalization and trafficking) are strongly associated with CAM-DR development.
Development of an adhesion model of established MM cell lines and detection of Numbl and Integrinβ1 expression by Western Blot analysis. The interaction between Numbl and Integrinβ1 was assessed by a co-immunoprecipitation (CO-IP) method. Calcein AM assay was performed to investigate the levels of cell adhesion. Finally, the extent of CAM-DR in myeloma cells was measured using cell viability assay and flow cytometry analysis.
Our preliminary date suggest that Numbl is differentially expressed in a cell adhesion model of MM cell lines. In addition to binding to the phosphotyrosine-binding (PTB) domain, the carboxyl terminal of Numbl can also interact with integrin β1 to regulate the cell cycle by activating the pro-survival PI3K/AKT signaling pathway. This study intends to verify and elucidate the interaction between Numbl and integrin β1 and its functional outcome on CAM-DR. We have designed and developed a CAM-DR model using MM cells coated with either fibronectin or bone marrow stromal cells. We assessed whether Numbl influences cell-cycle progression and whether it, in turn, contributes to activation of PI3K/AKT signal pathway through the adjustment of its carboxyl end. Finally, we showed that the interaction of Numbl with integrin β1 promotes the formation of CAM-DR in MM cells.
Our findings elucidated the specific molecular mechanisms of CAM-DR induction and confirmed that Numbl is crucial for the development of CAM-DR in MM cells.
Previous studies have demonstrated that activator of G-protein signaling 3 (AGS3; also known as GPSM1), a member of the AGS family, plays an important anti-apoptotic role through enhancing the ...phosphorylation of cyclic AMP response element-binding protein (p-CREB). In this report, we delineate the anti-apoptotic role of AGS3 in multiple myeloma (MM). To do this, we developed a cell apoptotic model induced by doxorubicin in MM. Our data indicate that decreased expression of AGS3 is correlated with reduced levels of p-CREB in the apoptotic model. The negative role of AGS3 in cell apoptosis was further confirmed by knocking down AGS3. The microenvironment has been shown to influence tumor cell phenotype in response to chemotherapy. Since cell adhesion-mediated drug resistance remains a major obstacle for successful treatment of MM, we constructed a cell adhesion model in MM and detected the changing of AGS3 protein expression. AGS3 siRNA reversed the high rate of MM cell adhesion to either fibronectin or HS-5 cells. Consistent with the reduced adhesion rate, the cells also exhibited reduced drug resistance to doxorubicin, mitoxantrone, and dexamethasone. Collectively, these data indicate that AGS3 may be represented as a good candidate for pursuing clinical trials in MM. Moreover, our data provide a clinical therapeutic target for MM and potentially other tumors that home and/or metastasize to the bone.
Previous studies have demonstrated that FoxJ2 (forkhead box J2) is a member of Forkhead Box transcription factors and acts as an important prognostic indicator in human breast cancer. Our study aimed ...to assess the expression and function in human glioma. Western blot analysis and immunohistochemistry were performed in human glioma tissues. Low FoxJ2 expression was observed in 80 samples and its level was correlated with the grade of malignancy. A strongly positive correlation was observed between FoxJ2 and E-cadherin. Overexpression of FoxJ2 increased E-cadherin expression and decreased vimentin expression. The wound healing and transwell assays showed that overexpression of FoxJ2 significantly inhibited their migration in U87 cells. Consistent with this, knockdown of FoxJ2 promoted cellular motility. In a word, FoxJ2 suppressed cell migration and invasion in glioma, which might be a potential novel molecular targeted therapy for surgery and immune treatment.
Glioma is the most common central nervous system tumor with poor prognosis. The AEG-1 (Astrocyte Elevated Gene 1) gene displays oncogenic characteristics, including proliferation, metastasis, ...chemoresistance, invasion, and evasion of apoptosis, and is strongly linked to the occurrence of glioma. Here, we elucidated the potential contribution of AEG-1 in human glioma pathogenesis. In glioma cells, AEG-1 could directly interact with Murine Double Minute-2 (MDM2) protein resulting in MDM2-p53-mediated cell proliferation and apoptosis. MDM2 is being revealed as an oncoprotein, which is involved in many human cancers progression. By immunohistochemical and a multivariate analysis, expressions of AEG-1 and MDM2 were elevated in glioma and high AEG-1 and MDM2 expressions were showed to be correlated with poor prognosis. AEG-1-MDM2 interaction prolonged stabilization of MDM2 where AEG-1 inhibited ubiquitination and subsequent proteasome-mediated degradation of MDM2 protein. Moreover, slicing AEG-1 blocked MDM2 expression and then impacted MDM2-p53 pathway that influenced cell proliferation and apoptosis. These findings uncover a novel AEG-1-MDM2 interplay by which AEG-1 augments glioma progression and reveal a viable potential therapy for the treatment of glioma patients.
The development of molecular pathogenesis of hepatocellular carcinoma (HCC) is complex and involves alterations in the expression and conformation of assorted oncoproteins and tumor suppressors. ...Chaperonin containing TCP1 (CCT) is a cytolic molecular chaperone complex that is required for the correct folding of numerous proteins. In this study, we investigated a possible involvement of CCT subunit 8 (CCT8) in HCC development. Immunohistochemical analysis was performed in 102 human HCC samples. High CCT8 expression was detected in clinical HCC samples compared with adjacent noncancerous tissues. The univariate and multivariate survival analyses were also performed to determine their prognostic significance. Western blot confirmed the high expression of CCT8 in HCC compared with adjacent normal tissue. Moreover, the biological significance of the aberrant expression of CCT8 was investigated in HCC cell lines. Expression of CCT8 was correlated directly with the histologic grades and tumor size of HCC and high expression of CCT8 was associated with a poor prognosis. CCT8 depletion by siRNA inhibited cell proliferation and blocked S‐phase entry in HuH7 cells. These results suggested that CCT8 might be an oncogene and participate in HCC cell proliferation. These findings provide a potential therapeutic strategy for the treatment of HCC.
Background
Human hepatocellular carcinoma (HCC) is one of the most common fatal cancers and an important health problem worldwide, but its mechanism is still unclear. Microtubule (MT) kinesin motor ...proteins orchestrate a variety of cellular processes (e.g. mitosis, motility and organelle transportation) and have been involved in human carcinogenesis. KIF3B, the kinesin superfamily of proteins (KIFs), plays an important role in the regulation of mitotic progression.
Aim
The expression of KIF3B and its involvement in HCC was investigated.
Methods
Western blot and immunohistochemistry were used to measure the expression of KIF3B protein in HCC and adjacent non-tumorous tissues in 57 patients and Cell Counting Kit-8 to analyze the effects of growth and interference of KIF3B in the cell cycle process.
Results
KIF3B protein level was increased in HCC tissues compared with the adjacent non-tumorous tissues. It was significantly associated with histological differentiation, tumor size, the level of alpha fetal protein (AFP) and proliferation marker Ki-67. Over-expression of KIF3B was correlated with poor survival. Following release of HepG2 cells from serum starvation, the expression of KIF3B was up-regulated. Furthermore, suppression of KIF3B not only decreased cancer cell growth but also induced apoptosis of cells.
Conclusions
Our results suggested that KIF3B expression was upregulated in HCC tumor tissues and proliferating HCC cells, and an increased KIF3B expression was associated with poor overall survival. KIF3B over-expression is involved in the pathogenesis of hepatocellular carcinoma and may serve as a potential therapeutic target for human HCC.
Glioblastoma multiforme (GBM), a grade-IV glioma, is resistant to TNF-α induced apoptosis. CLIPR-59 modulates ubiquitination of RIP1, thus promoting Caspase-8 activation to induce apoptosis by TNF-α. ...Here we reported that CLIPR-59 was down-regulated in GBM cells and high-grade glioma tumor samples, which was associated with decreased cancer-free survival. In GBM cells, CLIPR-59 interacts with Spy1, resulting in its decreased association with CYLD, a de-ubiquitinating enzyme. Moreover, experimental reduction of Spy1 levels decreased GBM cells viability, while increased the lysine-63-dependent de-ubiquitinating activity of RIP1 via enhancing the binding ability of CLIPR-59 and CYLD in GBM, thus promoting Caspase-8 and Caspase-3 activation to induce apoptosis by TNF-α. These findings have identified a novel Spy1-CLIPR-59 interplay in GBM cell's resistance to TNF-α-induced apoptosis revealing a potential target in the intervention of malignant brain tumors.
Cell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). In particular, the expression levels of integrin beta1 and its ...sub-cellular distribution (internalization and trafficking) are strongly associated with CAM-DR development. Development of an adhesion model of established MM cell lines and detection of Numbl and Integrinbeta1 expression by Western Blot analysis. The interaction between Numbl and Integrinbeta1 was assessed by a co-immunoprecipitation (CO-IP) method. Calcein AM assay was performed to investigate the levels of cell adhesion. Finally, the extent of CAM-DR in myeloma cells was measured using cell viability assay and flow cytometry analysis. Our preliminary date suggest that Numbl is differentially expressed in a cell adhesion model of MM cell lines. In addition to binding to the phosphotyrosine-binding (PTB) domain, the carboxyl terminal of Numbl can also interact with integrin beta1 to regulate the cell cycle by activating the pro-survival PI3K/AKT signaling pathway. This study intends to verify and elucidate the interaction between Numbl and integrin beta1 and its functional outcome on CAM-DR. We have designed and developed a CAM-DR model using MM cells coated with either fibronectin or bone marrow stromal cells. We assessed whether Numbl influences cell-cycle progression and whether it, in turn, contributes to activation of PI3K/AKT signal pathway through the adjustment of its carboxyl end. Finally, we showed that the interaction of Numbl with integrin beta1 promotes the formation of CAM-DR in MM cells. Our findings elucidated the specific molecular mechanisms of CAM-DR induction and confirmed that Numbl is crucial for the development of CAM-DR in MM cells.
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