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Recently, calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP), a component of a novel ubiquitinylation pathway, could regulate the b-catenin degradation (Fukushima et al., Immunity 2006, 24, 29 -39). However, the potential role of CacyBP/SIP itself in human glioma cells has not been clarified. Here, we found that CacyBP/SIP was expressed highly in human glioma tissues. Silencing of CacyBP/SIP by short-hairpin RNA severely suppressed the proliferation of human glioma cell U251, which was at least partly mediated by downregulation of phospho-Akt (p-Akt) and phospho-b-catenin (p-b-catenin) as well as upregulation of p53 and p21. Furthermore, overexpression of CacyBP/SIP obviously promoted the proliferation of human glioma U251, which exhibited the exactly contrary trend in the expression of p-Akt, p-b-catenin, p53, and p21. Taken together, these findings suggest that CacyBP/SIP plays important roles in the proliferation of human glioma cell which might be involved in the development of human glioma. V C 2014 IUBMB Life, 66(4): [286][287][288][289][290][291] 2014

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It has been reported that by regulating PHD3 stability, Siah1 contributes to the abundance of hypoxia-inducible factor (HIF)-1α, thereby playing an important role in the cellular response to hypoxia. However, the expression level and functional significance of Siah1 in human malignant glioma, which is characterized by high migration and invasion potential, have never been investigated. We report here, that Siah1 was expressed highly in human glioma tissues compared with its expression in normal brain tissues and was correlated with advanced tumor status and stage. The knockdown of Siah1 by short-hairpin RNA severely suppressed the migration and invasion of human glioma U251 cells under hypoxia, while overexpression of Siah1 promoted it. Furthermore, we demonstrated that the glioma cell migration and invasion under hypoxia mediated by Siah1 was achieved by reducing the stability of PHD3, which protected the HIF-1α from degradation. These findings suggest that Siah1 plays important roles in the migration and invasion of human glioma cells under hypoxia, which may provide some guidance for the targeted therapy of human glioma based on the interference of the Siah1-PHD3-HIF-1α signaling pathway.

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The RAS signaling pathway is hyperactive in malignant glioma due to overexpression and/or increased activity. A previous study identified that RASD1, a member of the RAS superfamily of small G-proteins, is a significantly dysregulated gene in oligodendroglial tumors that responded to chemotherapy. However, the role and mechanism of RASD1 in the progression of human glioma remain largely unknown. In the present study, by analyzing a public genomics database, we found that high levels of RASD1 predicted good survival of astrocytoma patients. We thus established lentivirus-mediated RASD1-overexpressing glioma cells and found that overexpressing RASD1 had no significant effects on glioma cell proliferation. However, the overexpression of RASD1 inhibited glioma cell migration and invasion. In the intracranial glioma xenograft model, the overexpression of RASD1 significantly reduced the number of tumor cells invading into the surrounding tissues without affecting the tumor size. An intracellular signaling array revealed that the phosphorylation of both AKT and the S6 ribosomal protein significantly decreased with RASD1 overexpression in glioma cells. Interestingly, RASD1 protein levels were significantly higher in grade II and grade III astrocytoma tissues than in nontumorous brain tissues. These findings suggest that the upregulation of RASD1 in glioma tissues may play an inhibitory role in tumor expansion, possibly through inactivating the AKT/mTOR signaling pathway.

SH3GL2 (Src homology 3 (SH3) domain GRB2‐like 2) is mainly expressed in the central nervous system and regarded as a tumour suppressor in human glioma. However, the molecular mechanism of the SH3GL2 protein involved in malignant behaviours of human glioma has not been elucidated. In this study, we tried to investigate the role of SH3GL2 in glioma cell migration and invasion and explore its underlined molecular mechanism. Firstly, we discovered that the protein level of SH3GL2 was widely decreased in the human glioma patients, especially in high‐grade glioma tissues. Then, we determined the role of SH3GL2 in migration and invasion of glioma cells upon SH3GL2 knocking down and overexpressing. It was showed that knocking down of SH3GL2 promoted the migration and invasion of glioma cells, whereas overexpression of SH3GL2 inhibited them. Further study on molecular mechanism disclosed that silencing of SH3GL2 obviously activated the STAT3 (signal transducer and activator of transcription 3) signalling thereby promoting the expression and secretion of MMP2. On the contrary, overexpression of SH3GL2 had opposite effect. Taken together, the above results suggest that SH3GL2 suppresses migration and invasion behaviours of glioma cells through negatively regulating STAT3/MMP2 signalling and that loss of SH3GL2 may intensify the STAT3/MMP2 signalling thereby contributing to the migration and invasion of glioma cells.