KIF4A drives gliomas growth by transcriptional repression of Rac1/Cdc42 to induce cytoskeletal remodeling in glioma cells.

Glioma is one of the most prevalent cancers diseases in the worldwide. Kinesin superfamily protein 4 (KIF4), a KIF member classified in Kinesin 4 has been indicated as a mediator acted in tumorigenesis of human cancer. However, the mechanism of KIF4A on glioma is yet to be investigated. This study aimed to explore the potential function and mechanism of KIF4A in gliomas. We analyzed the KIF4A expression and the prognosis in gliomas patients using The Cancer Genome Atlas (TCGA) databases. KIF4A level in normal human astrocyte cell (NHA) and glioma cell lines were examined by Western blot. We studied the function of KIF4A on proliferation, migration, invasion, cell cycle in glioma cell lines using a series of in vitro and in vivo experiments. Chromatin Immunoprecipitation (ChIP) analysis was applied to searching potential KIF4A related downstream in glioma. We identified the significant up-regulated expression of KIF4A both in glioma tissues and cell. Glioma patients with elevated KIF4A expression have shorter survival. Down-regulation of KIF4A exerted inhibitory effect on cell proliferation, invasion and migration. We crucially identified that KIF4A drives gliomas growth by transcriptional repression of Rac1/Cdc42 to induce cytoskeletal remodeling in glioma cells. Knockdown of KIF4A decreased RohA, Rac1, Cdc42, Pak1 and Pak2 expression level. Our study provided a prospect that KIF4A functions as an oncogene in glioma.

Relationship between expression of XRCC1 and tumor proliferation, migration, invasion, and angiogenesis in glioma.

Recently, XRCC1 polymorphisms were reported to be associated with glioma in Chinese population. However, only a few studies reported on the XRCC1 expression, and cancer progression. In this study, we investigated whether XRCC1 plays a role in glioma pathogenesis. Using the tissue microarray technology, we found that XRCC1 expression is significantly decreased in glioma compared with tumor adjacent normal brain tissue (P < 0.01, χ2 test) and reduced XRCC1 staining was associated with WHO stages (P < 0.05, χ2 test). The mRNA and protein levels of XRCC1 were significantly downregulated in human primary glioma tissues (P < 0.001, χ2 test). We also found that XRCC1 was significantly decreased in glioma cell lines compared to normal human astrocytes (P < 0.01, χ2 test). Overexpression of XRCC1 dramatically reduced the proliferation and caused cessation of cell cycle. The reduced cell proliferation is due to G1 phase arrest as cyclin D1 is diminished whereas p16 is upregulated. We further demonstrated that XRCC1 overexpression suppressed the glioma cell migration and invasion abilities by targeting MMP-2. In addition, we also found that overexpression of XRCC1 sharply inhibited angiogenesis, which correlated with down-regulation of VEGF. The data indicate that XRCC1 may be a tumor suppressor involved in the progression of glioma.

CTHRC1 mediates multiple pathways regulating cell invasion, migration and adhesion in glioma.

Recently, collagen triple helix repeat containing-1 (CTHRC1) has been reported to be increased in several types of human solid cancers and to be associated with tumor invasion and metastasis. However, the expression and function of CTHRC1 in glioma have not yet been reported. In the present study, we investigated whether CTHRC1 plays a role in glioma pathogenesis. Using the tissue microarray technology, we found that CTHRC1 expression is significantly increased in glioma compared with tumor adjacent normal brain tissue (P<0.01, χ2 test) and increased CTHRC1 staining was associated with WHO stages (P<0.05, χ2 test). The mRNA and protein levels of CTHRC1 were significantly upregulated in human primary glioma tissues (P<0.001, χ2 test). We also found that CTHRC1 was significantly increased in glioma cell lines compared to normal human astrocytes (P<0.01, χ2 test). Furthermore, Knockdown of CTHRC1 suppressed glioma cell invasion and inhibited enzyme activity of MMP-2. Moreover, our data showed that knockdown of CTHRC1 inhibited glioma cell migration and adhesion capacity when compared with the control cells, and CTHRC1-siRNA reduced the levels of phosphorylated Src and FAK protein expression. Taken together, this study suggests that CTHRC1 plays a role in glioma development and progression by regulating invasion, migration and adhesion capabilities of cancer cells.

Overexpression of CAP1 and its significance in tumor cell proliferation, migration and invasion in glioma.

Adenylate cyclase-associated protein 1 (CAP1), a protein related to the regulation of actin filaments and the Ras/cAMP pathway, is associated with tumor progression. Nevertheless, the expression level and effects of CAP1 in regards to glioma have not been reported. In the present study, we examined the expression of CAP1 in glioma and tumor adjacent normal brain tissues by tissue microarray and immunohistochemistry. Our results showed that CAP1 was overexpressed in glioma tissues in comparison with that noted in the tumor adjacent normal brain tissues and increased staining of CAP1 was found to be correlated with WHO stage. In addition, we discovered that knockdown of CAP1 by specific RNA interference markedly inhibited cell growth and caused downregulation of the proliferation markers, PCNA and cyclin A. We further demonstrated that knockdown of CAP1 inhibited cell metastatic abilities by downregulating N-cadherin and vimentin and upregulating E-cadherin. These findings revealed that CAP1 expression is markedly increased in human glioma and that downregulation of CAP1 in tumors may serve as a treatment for glioma patients.

Cullin1 regulates proliferation, migration and invasion of glioma cells.

This study was designed to explore the role of Cullin1 (Cul1) in the pathogenesis of human glioma and to investigate the role of Cul1 in the growth, migration and invasion of glioma cells. Expression of Cul1 in 191 glioma tissues, 8 normal brain tissues and 8 tumor adjacent normal brain tissues was analyzed by tissue microarray and immunohistochemistry. Cul1 expression in human glioblastoma cells was knocked down by specific siRNA to study the effect of down-regulation of Cul1 on proliferation, invasion and migration of glioma cells. Our results showed that Cul1 expression increased significantly in tissues from the benign tumor and malignant tumor in comparison with those from the tumor-adjacent normal brain (P<0.05 for both). We did not find any correlation between Cul1 expression and clinicopathological parameters. In addition, we found that knockdown of Cul1 by RNA interference markedly inhibited cell proliferation and caused cessation of cell cycle. This reduced cell proliferation was due to G1 phase arrest as cyclinA, cyclinD1 and cyclinE were diminished, whereas p21 and p27 were up-regulated. We further demonstrated that silencing of Cul1 in glioma cells inhibited the cell migration and invasion abilities, and down-regulation of MMP-2 and MMP-9 expression greatly contributed to the reduced cell invasion and migration abilities. Our data indicated that Cul1 expression significantly increased in human glioma, and it may be involved in proliferation, migration and invasion of glioma cells.

MiR-29c inhibits glioma cell proliferation, migration, invasion and angiogenesis.

Previous studies reported that miR-29c is significantly downregulated in several tumors. However, little is known about the effect and molecular mechanisms of action of miR-29c in human glioma. Using quantitative RT-PCR, we demonstrated that miR-29c was significantly downregulated in glioma cell lines and human primary glioma tissues, compared to normal human astrocytes and matched non-tumor associated tissues (P < 0.05, χ(2) test). Overexpression of miR-29c dramatically reduced the proliferation and caused cessation of cell cycle. The reduced cell proliferation is due to G1 phase arrest as cyclin D1 and cyclin E are diminished whereas p27 and p21 are upregulated. We further demonstrated that miR-29c overexpression suppressed the glioma cell migration and invasion abilities by targeting MMP-2. In addition, we also found that overexpression of miR-29c sharply inhibited angiogenesis, which correlated with down-regulation of VEGF. The data indicate that miR-29c may be a tumor suppressor involved in the progression of glioma.

[Application of diffusion tensor imaging in preoperation and postoperation patients of glioma with 3.0 Tesla MRI].

OBJECTIVE: To investigate the clinical usefulness of diffusion tensor imaging (DTI) in demonstrating between gliomas and surrounding fibers. METHODS: 24 patients of glioma (WHO grade: grade I - II 16 cases; grade III - IV 8 cases) were examined using DTI and conventional contrast-enhanced MRI of 3.0 T MRI scanner (GE company, America). After the initial data acquisition introduced into workstation, image analysis was performed with the use of functool software. Mean diffusivity (MD) and fractional anisotropy (FA) values were measured in regions of solid tumor, surrounding edema and normal white matter of the high grade cerebral gliomas. Differences in these values among the tissues were assessed on the high grade cerebral gliomas. Anatomic relationship between intracranial tumors and surrounding fibers was analysed on fractional anisotropic (FA) map, color-coded directional map, three-dimensional white matter tractography. All patients' symptoms were evaluated preoperative and postoperative respectively. RESULTS: The DTI patterns altered by the tumor were categorized as follows: displacement, infiltration and destruction. The tractography showed that the main influence in 16 cases of grade I - II glioma on adjacent white matter tracts was displacement, but infiltration and destruction were also revealed. The patients have definite improvement in symptoms. The destruction and infiltration of fiber tracts could be seen in all edema regions around grade III - IV gliomas in 8 cases. The patients have not definite improvement in symptoms. Apparently significant differences of MD were found in solid tumor, surrounding edema, compared with normal white matter regions (P < 0.05). But there was no significant difference among solid tumor and surrounding edema region (P > 0.05). There were significant differences of FA between solid tumor, surrounding edema and normal white matter region (P < 0.05). CONCLUSIONS: The DTI offered the optimal visualization of white matter tracts. DTI plays an important role in demonstrating relationship between gliomas and neighboring fibers. MD and FA values could be used to distinguish normal white matter from solid tumor and surrounding edema region of high grade glioma. The application of DTI in preoperation plays an guidance role in making microsurgery plans and the evaluation of brain functional recovery in postoperation. DTI should be of great value in the microsurgical planning as well as estimation and reduction of potential postoperative neurological deficits for the cerebral gliomas resection.