Caveolin-1 promotes glioma proliferation and metastasis by enhancing EMT via mediating PAI-1 activation and its correlation with immune infiltrates.

Glioma is typically characterized by a poor prognosis and is associated with a decline in the quality of life as the disease advances. However, the development of effective therapies for glioma has been inadequate. Caveolin-1 (CAV-1) is a membrane protein that plays a role in caveolae formation and interacts with numerous signaling proteins, compartmentalizing them in caveolae and frequently exerting direct control over their activity through binding to its scaffolding domain. Although CAV-1 is a vital regulator of tumour progression, its role in glioma remains unclear. Our findings indicated that the knockdown of CAV-1 significantly inhibits the proliferation and metastasis of glioma. Subsequent mechanistic investigations demonstrated that CAV-1 promotes proliferation and metastasis by activating the photoshatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Furthermore, we demonstrated that CAV-1 overexpression upregulates the expression of serpin peptidase inhibitor, class E, member 1 (SERPINE1, also known as PAI-1), which serves as a marker for the epithelial-mesenchymal transition (EMT) process. Further research showed that PAI-1 knockdown abolished the CAV-1 mediated activation of PI3K/Akt signaling pathway. In glioma tissues, CAV-1 expression exhibited a correlation with unfavorable prognosis and immune infiltration among glioma patients. In summary, our study provided evidence that CAV-1 activates the PI3K/Akt signaling pathway by upregulating PAI-1, thereby promoting the proliferation and metastasis of glioma through enhanced epithelial-mesenchymal transition (EMT) and angiogenesis, and CAV-1 is involved in the immune infiltration.

Exosomes Derived from Hypoxic Glioma Cells Reduce the Sensitivity of Glioma Cells to Temozolomide Through Carrying miR-106a-5p.

Background: Hypoxia is a frequent feature of solid tumors which significantly affects the efficacy of treatments such as chemotherapy. In addition, exosomes from hypoxic cancer cells could contribute to the chemoresistance of tumor cells through carrying miRNAs. It has been shown that miR-106-5p level was upregulated in glioma. However, whether exosomes derived from hypoxic glioma cells could affect temozolomide (TMZ) resistance in glioma through carrying miR-106a-5p remains unexplored. Methods: Exosomes were isolated from glioma cells under normoxia or hypoxia condition. EdU staining and flow cytometry assays were used to assess the cell proliferation and cell apoptosis. The relation between miR-106a-5p and PTEN was investigated by dual luciferase assay. Results: MiR-106a-5p was enriched in exosomes derived from hypoxic glioma cells compared to exosomes from cells under normoxia condition. Additionally, hypoxic glioma cells were able to transfer exosomes to glioma cells, resulting in a significant increase of miR-106a-5p level in cells. TMZ remarkably suppressed glioma cell proliferation and triggered cell apoptosis. However, hypoxic glioma cell-derived exosomes markedly promoted the proliferation and suppressed the apoptosis in TMZ-treated glioma cells, and miR-106a-5p inhibitor was able to abolish these phenomena. Meanwhile, PTEN was verified to be a direct target of miR-106a-5p. Furthermore, TMZ elevated PTEN and Bax level and reduced p-Akt level in glioma cells, whereas these changes were reversed by hypoxia glioma cell-derived exosomes. Furthermore, hypoxia glioma cell-derived exosomes reduced the sensitivity of glioma cells to TMZ in vivo via downregulating PTEN. Conclusion: Collectively, exosomal miR-106a-5p derived from hypoxia glioma cells could reduce the sensitivity of glioma cells to TMZ through downregulating PTEN. Thus, our study might provide new strategies for improving the clinical efficacy of TMZ on glioma.

DTX3L is upregulated in glioma and is associated with glioma progression.

Gliomas are the most common primary brain tumors of the central nervous system (CNS). Due to the poor prognosis of glioma patients, it is urgent to develop more effective therapies. Deltex-3-like (DTX3L), also known as B-lymphoma and BAL-associated protein (BBAP), has been reported to play an important role in the progression of many tumors. This study aimed to investigate the clinical significance and biological function of DTX3L in human glioma. Clinically, the protein expression level of DTX3L is increased in glioma tissues compared with that observed in normal brain tissues. Immunohistochemical analysis demonstrated that DTX3L was highly expressed in the glioma tissues and its level was correlated with the grade of malignancy. Multivariate analysis revealed the association between high expression of DTX3L and the poor prognosis of glioma patients. In addition, knockdown of DTX3L by siRNA transfection increased glioma cell apoptosis. Moreover, suppression of DTX3L expression was shown to significantly inhibit the migration and invasion of glioma cells. These data indicate that DTX3L plays an important role in the pathogenic process of glioma, suggesting that DTX3L could be a potential prognostic biomarker for glioma.

High expression of PIWIL2 promotes tumor cell proliferation, migration and predicts a poor prognosis in glioma.

Piwi-like RNA-mediated gene silencing 2 (PIWIL2), has been reported as an oncogene tightly associated with the genesis and progression of various malignancies. Nevertheless, the function of the PIWIL2 protein in human gliomas has not yet been clarified. In this study, we sought to investigate the clinical significance of PIWIL2 expression and reveal its function in the pathological process of gliomas. Through western blot and immunohistochemical analyses we found that PIWIL2 was overexpressed in glioma tissues. Moreover, the expression level of PIWIL2 was also significantly correlated with the WHO grades of human gliomas and Ki-67 expression. Kaplan­Meier curves indicated that PIWIL2 was a prognostic factor for the survival of glioma patients and a high expression of PIWIL2 was correlated with a poor prognosis. In vitro, knockdown of PIWIL2 in glioma cells was shown to induce cell cycle arrest and increase apoptosis. Furthermore, silencing of PIWIL2 expression also obviously suppressed the migration of glioma cells. All the results demonstrated that PIWIL2 plays a significant role in the pathogenesis of human gliomas and may be used as a potential diagnostic marker and a therapeutic target of glioma in the future.

Silencing of OTUB1 inhibits migration of human glioma cells in vitro.

OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) protein, a deubiquitinating enzyme (DUB) which belongs to the ovarian tumor (OTU) family, was reported to be associated with the development of various malignancies. However, the potential function of OTUB1 in human gliomas was still unclear. In this study, we sought to investigate the function of OTUB1 in the pathological process of gliomas and analyze its related clinical significance. Western blot and immunohistochemistry analyses demonstrated that OTUB1 was overexpressed in glioma tissues, and statistical analysis suggested the expression level of OTUB1 was significantly correlated with the WHO grades of human gliomas (P < 0.05). Moreover, Kaplan-Meier curve also indicated that high expression of OTUB1 was correlated with a poor prognosis. In vitro, silencing OTUB1 retarded the migration ability of glioma cells. Knockdown of OTUB1 increases epithelial-mesenchymal transition-related protein E-cadherin expression, but decreases simultaneously the expression of vimentin and snail. Furthermore, down-regulated expression of OTUB1 also resulted in decreased expression of some extracellular matrix degradation-related proteins, such as matrix metallopeptidase (MMP)2 and MMP9. All results suggested that OTUB1 was a valuable marker in the pathogenesis of human gliomas and could be used as a novel biomarker for glioma therapy in the future.