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SU4312, initially designed as a multi-target tyrosine kinase inhibitor, is consequently reported to inhibit tumor angiogenesis by blocking VEGFR. However, although SU4312 can penetrate the brain–blood barrier, its potential to inhibit glioma growth is unknown. In this study, we report that SU4312 inhibited glioma cell proliferation and down-regulated yes-associated protein (YAP), the key effector of the hippo pathway. The exogenous over-expression of YAP partially restored the inhibitory effect of SU4312 on glioma progression. Interestingly, SU4312 sensitized the antitumor effect of temozolomide, both in vitro and in vivo. Moreover, SU4312 decreased the M2tumor-associated macrophages and enhanced anti-tumor immunity by down-regulating the YAP-CCL2 axis. In conclusion, our results suggest that SU4312 represses glioma progression by down-regulating YAP transcription and consequently CCL2 secretion. SU4312 may be synergistic with temozolomide for glioma treatment. [ABSTRACT FROM AUTHOR]

Background/Aims: Golgi phosphoprotein 3 (GOLPH3) plays pro-malignancy roles in several types of cancer. However, the molecular mechanism underlying GOLPH3 promoting tumor progression remains poorly understood. Methods: The expression of GOLPH3 and Wntless (Wls) in glioma tissues was examined by western blotting and immunohistochemistry. EdU incorporation assay and colony formation assay was used to examine the cell growth ability. The effect of GOLPH3 on Wls recycling, Wnt secretion and β-catenin activity was detected using western blotting, immunofluorescence, RT-PCR, ELISA or luciferase assay. Results: The protein levels of GOLPH3 and Wls were upregulated and positively correlated with each other in human glioma tissues. The promoting effect of GOLPH3 on glioma cell proliferation was partially mediated by Wls. In addition, GOLPH3 interacted with Wls and GOLPH3 down-regulation drove Wls into lysosome for degradation, inhibiting its recycling to golgi and the plasma membrane. Importantly, GOLPH3 down-regulation inhibited Wnt2b secretion and decreased β-catenin level and transcription activity. Conclusions: This study provides a brand new evidence that GOLPH3 promotes glioma cell proliferation by facilitating Wls recycling and Wnt/β-catenin signaling. Our findings suggest a rationale for targeting the GOLPH3-Wls-Wnt axis as a promising therapeutic approach for glioblastoma. [ABSTRACT FROM AUTHOR]

Wnt signaling has been identified as a critical regulator of human tumor development in vitro. However, there remains a lack of studies systematically examining the expression pattern and clinical relevance of the core molecules of Wnt signaling in glioma tissues. In the present study, it was identified that the mRNA expression levels of Wnt3a and 5a, and their receptors frizzled 2, 6 and 7 increased, whereas Wnt7b was markedly decreased in glioma relative to non-tumor tissue. The mRNA levels of β-catenin, adenomatous polyposis coli gene product, glycogen synthase kinase 3β (GSK3β) and AXIN1 and its target genes cyclin D1 and AXIN2 did not differ. Similarly, the protein levels of Wnt2b, 3a and 5a were increased in gliomas, while β-catenin, GSK3β and cyclin D1 were not. Furthermore, based on data from the R2: Genomics Analysis and Visualization Platform, the expression of Wnt2b and 5a, and frizzled 2, 6 and 7 were highly associated with the prognosis of patients with glioma. Taken together, the results of the present study demonstrate that β-catenin is not upregulated in gliomas and that the Wnt signaling pathway may promote glioma development via noncanonical or alternative pathways. [ABSTRACT FROM AUTHOR]

Bmi-1 is involved in the development of several human cancers; however, its significance in glioma progression remains largely unknown. We report that downregulation of Bmi-1 clearly reduces glioma cell migration and invasion. Downregulation of Bmi-1 promotes the expression of the tumor suppressor p16, which is important in glioma cell motility. Reduction in glioma cell invasion due to downregulation of Bmi-1 could be rescued by p16 downregulation. These results show that Bmi-1 contributes to the motility of glioma cells by regulating the expression of p16. [ABSTRACT FROM AUTHOR]

Highlights: [•] GOLPH3 downregulation induced a distinct reduction of glioma cell motility. [•] GOLPH3 downregulation inhibited the expression of RhoA. [•] GOLPH3 downregulation suppressed cytoskeleton reorganization. [•] RhoA overexpression rescued GOLPH3 knockdowning induced cell migration. [ABSTRACT FROM AUTHOR]

Abstract: The function of Bex2, a member of the Brain Expressed X-linked gene family, in glioma is controversial and its mechanism is largely unknown. We report here that Bex2 regulates cell proliferation and apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase (JNK) pathway. The expression level of Bex2 is markedly increased in glioma tissues. We observed that Bex2 over-expression promotes cell proliferation, while down-regulation of Bex2 inhibits cell growth. Furthermore, Bex2 down-regulation promotes cell apoptosis and activates the JNK pathway; these effects were abolished by administration of the JNK specific inhibitor, SP600125. Thus, Bex2 may be an important player during the development of glioma. [Copyright &y& Elsevier]

Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) plays a great role in tumor cell growth, but its function and mechanism in cell invasive behavior are totally unknown. Here we report that NEDD4-1 regulates migration and invasion of malignant glioma cells via triggering ubiquitination of cyclic nucleotide Ras guanine nucleotide exchange factor (CNrasGEF) using cultured glioma cells. NEDD4-1 overexpression promoted cell migration and invasion, while its downregulation specifically inhibited them. However, NEDD4-1 did not affect the proliferation and apoptosis of glioma cells. NEDD4-1 physically interacted with CNrasGEF and promoted its poly-ubiquitination and degradation. Contrary to the effect of NEDD4-1, CNrasGEF downregulation promoted cell migration and invasion, while its overexpression inhibited them. Importantly, downregulation of CNrasGEF facilitated the effect of NEDD4-1-induced cell migration and invasion. Interestingly, aberrant up-regulated NEDD4-1 showed reverse correlation with CNrasGEF protein level but not with its mRNA level in glioma tissues. Combined with the in vitro results, the result of glioma tissues indicated post-translationally modification effect of NEDD4-1 on CNrasGEF. Our study suggests that NEDD4-1 regulates cell migration and invasion through ubiquitination of CNrasGEF in vitro. [ABSTRACT FROM AUTHOR]

Previously, we found that brain expressed X-linked gene 2 (Bex2) regulates the invasion/migration ability of glioma cells. However, the mechanism of this effect remains unknown. In current study, we reported that Bex2 down-regulation inhibited glioma cell migration and invasion by decreasing the nucleus and cytoplasm protein level of β-catenin. We found that the protein levels of Bex2 and β-catenin were up-regulated and showed direct correlation in glioma tissues. Bex2 down-regulation significantly decreased β-catenin protein levels but not its mRNA levels. Furthermore, the decreased protein level of β-catenin was located in the nucleus and cytoplasm but not in the cell membrane. Further study found that the effects of Bex2 down-regulation on the invasion and migration of glioma cell could be reversed by β-catenin over-expression. Taken together, Bex2 affects the invasion and migration ability of glioma cells by regulating β-catenin. [ABSTRACT FROM AUTHOR]