Pathological Grade Of Glioma Research Articles

Overexpression of Golgi phosphoprotein-3 (GOLPH3) in glioblastoma multiforme is associated with worse prognosis

Golgi phosphoprotein-3 (GOLPH3), an important protein in mammalian target of rapamycin (mTOR) signaling, is overexpressed in and correlates with the pathological grade of glioma. However, the potential correlation between GOLPH3 and clinical outcome in patients with glioblastoma multiforme (GBM) remains unknown. In this study, we examined GOLPH3 expression in GBM by tissue microarray and correlated this measure to patient outcome. GOLPH3 expression in tumor tissue from 97 primary GBM patients was examined by tissue microarray and immunohistochemistry. Potential effects of GOLPH3 on tumor growth were also examined in representative cell lines (U251 and U87) by downregulating GOLPH3 with RNA interference. For this cohort, the median overall survival (OS) was 12 months [95 % confidence interval (CI): 10.31-13.69 months], and the median progression-free survival (PFS) was 10 months (95 % CI: 7.33-12.67 months). Tissue microarray analysis revealed high GOLPH3 expression in 40 patients (40/97, 41.2 %) and low GOLPH3 expression in the remaining 57 patients (57/97, 58.8 %). Log-rank test showed that patients with low GOLPH3 expression had significantly longer median OS (15 versus 10 months in patients with high GOLPH3 expression, p = 0.009) and median PFS (12 versus 7 months, p = 0.015). Univariate and Cox analysis indicated that GOLPH3 was an independent prognostic factor for OS and PFS. In in vitro experiments, GOLPH3 downregulation by small interfering RNA (siRNA) suppressed proliferation and clonogenic growth in cultured cell lines. These findings demonstrate that high GOLPH3 expression is associated with poor outcome of GBM patients.

Silencing of IKKε using siRNA inhibits proliferation and invasion of glioma cells in vitro and in vivo

Recent studies implicated IKKε in the pathogenesis of many human cancers by promoting cell proliferation, increasing tumor angiogenesis and metastasis, and generating resistance to cell apoptosis. However, whether IKKε can influence the invasive ability and proliferation of glioma cells remains largely unknown. In this study, we showed that overexpression of IKKε is positively correlated to glioma pathological grade, suggesting that IKKε plays a role in tumor progression, rather than tumor initiation. Targeted knockdown of IKKε in human glioma cells using siRNA, was associated with inhibition of cell growth, cell cycle arrest and decreased cell invasion; however, notable apoptosis was not observed. Furthermore, we demonstrated that transposition of NF-κB p65 resulted in the alteration of these phenotypes. Tumor growth was attenuated in established subcutaneous gliomas in nude mice treated with IKKε siRNA in vivo. Collectively, our results suggest that deregulation of IKKε plays a pivotal role in the uncontrolled proliferation and malignant invasion of glioma cells in vitro and in vivo by targeting NF-κB. Silencing of IKKε using synthetic siRNAs may offer a novel therapeutic strategy for the treatment of glioma.

Human brain glioma stem cells are more invasive than their differentiated progeny cells in vitro

Glioma, the most commonly occurring primary intracranial tumor, remains associated with a dismal outcome, despite the availability of multimodal therapies. Recently, however, the identification of brain glioma stem cells (BGSC) has opened up new avenues for research. BGSC are now accepted as the progenitor cells of gliomas and are thought to determine the biological features of the resulting tumors. Thus, the diffuse invasiveness of gliomas should also be theoretically driven by BGSC. However, little research effort has been directed at understanding the invasiveness of BGSC. In the present study, BGSC from eight surgical glioma specimens were cultured and identified. Using Matrigel invasion assays, the invasiveness of these cells was measured and compared with that of their respective differentiated progeny cells in vitro. For all eight clinical specimens, the BGSC were significantly more invasive than their differentiated progeny cells. These findings indicate a key role for BGSC in glioma infiltration and invasion. We also found that BGSC tended to aggregate and reform into new spheres after travelling into the Matrigel, preserving some of the morphological characteristics of the suspended cells. The invasiveness of the BGSC did not correlate with the pathological grade of glioma in the present study, so further investigations using larger sample sizes are needed to better understand the mechanisms underlying the invasiveness of BGSC.

Expression and distribution characteristics of human ortholog of mammalian enabled (hMena) in glioma

To investigate the utility of hMena, a family of enabled/vasodilator-stimulated phosphoprotein (Ena/VASP), we sought to characterize the expression profile and distribution characteristics of hMena in a large panel of glioma samples and determine whether hMena expression levels might correlate with the pathological grade of glioma. Sixty-five specimens of glioma with different pathological grades and five control brain tissues were collected. In 6 of the 21 glioblastoma patients, multi-specimens were obtained respectively from the main tumor mass, the junction zone between the tumor and the normal tissue, and adjacent brain tissue 1.5 cm away from the tumor boundary under assistance of neuronavigation system during the operation. Immunohistochemistry was used to detect the expression and distribution characteristics of hMena. hMena expression was analyzed by Western blot in 20 specimens. The hMena expression was negative in control brain tissue but positive in different grades of glioma. The expression rate of hMena was positively correlated with the increasing grade of the World Health Orgnization (WHO) classification (r(s)=0.682, P=0.000). hMena was located in cytoplasm. Positive cells only distributed around the vessels within the tumor mass in low grade glioma, while in high grade glioma, these cells were able to be detected not only in the tumor but also in the boundary zone and adjacent brain parenchyma. In the tumor mass, hMena expressed highly and diffusedly. In the junction zone, hMena positive cells formed radiolitic pattern around the vessels. In adjacent brain parenchyma, single positive cell was scattered. hMena expression was markedly elevated in Grade III and IV glioma compared with Grade II and I. Our data suggested that the expression of hMena is closely related to malignant grade of glioma. hMena can label the migrating cells, and indicate the migrating path of glioma cells from the tumor to adjacent tissue along with the vascular basement membranes and tracts of white matter.

MicroRNA-10b induces glioma cell invasion by modulating MMP-14 and uPAR expression via HOXD10

MicroRNAs are small endogenous noncoding RNAs, which modulate target gene expression by binding with target mRNA sequences in the 3′untranslated region (UTR) with an imperfect complementarity that inhibits the mRNA translation. Many microRNAs have been reported to function as tumor oncogenes or anti-oncogenes. Recently, more and more microRNAs have been reported to contribute to a tumor's invasive potential. Here, we show that microRNA-10b (miR-10b) was over-expressed in glioma samples and directly associated with the glioma's pathological grade and malignancy. We also found that miR-10b induced glioma cell invasion by modulating tumor invasion factors MMP-14 and uPAR expression via the direct target HOXD10. The miR-10b/HOXD10/MMP-14/uPAR signaling pathway might contribute to the invasion of glioma. Accordingly, glioma cells lost their invasive ability when treated with specific antisense oligonucleotides (miR-10b inhibitors), suggesting that miR-10b could be used as a new bio-target to cure glioma.

Expression and significance of ATP-binding cassette superfamily G member 2 and its relation to nestin in human gliomas

Objective To study the expression of ATP-binding cassette superfamily G member 2 ( ABCG2) and its relationship with the malignant degree and expression of nestin in human gliomas. Methods Fifty-two gliomas of different WHO grades and 8 normal brain tissues were detected for the mRNA expression of ABCG2 by using real-time quantitive polymerase chain reaction (PCR). And the protein expression of ABCG2 and nestin was detected by immunohistochemistry. Results The mRNA of ABCG2 was overexpressed in gliomas as compared with that in normal brain tissues (P<0. 05), and up-regulated with the increase of pathologic degrees (P<0. 05 ). The positive protein expression rate of ABCG2 in 52 gliomas was 32.7%. The positive rate was significantly higher in grade Ⅲ-Ⅳ than in grade Ⅰ -Ⅱ (x2 =4. 62, P < 0. 05). And the expression level of ABCG2 was obviously related with the expression of nestin (x2= 7. 60,P < 0.05). Conclusion The expression level of ABCG2 was obviously related with glioma pathological grade and the expression of nestin. Brain tumor stem cells may have some homology with nerve stem cells. Key words: Glioma; Brain tumor stem cell; Nestin

Study of correlation between expression of bradykinin B2 receptor and pathological grade in human gliomas

In clinical practice there is a difference in response of the blood-tumour barrier (BTB) permeability induced by bradykinin in brain tumours with the same pathology. The variability in response of tumours to bradykinin is likely to be related to the expression level of bradykinin B2 receptor. This study used fresh human glioma samples to determine the expression level of bradykinin B2 receptor on gliomas with different pathological grades. The grade of tumour was classified using the WHO classification. To determine the bradykinin B2 receptor expression level in gliomas, Immunohistochemistry and Western blot methods were used. In 24 cases of gliomas there were eight cases of WHO I glioma, eight cases of WHO II glioma and eight cases of WHO III glioma. Both Western blot and immunohistochemistry showed bradykinin B2 receptors localized on tumour cells, whilst brain cells at the edge of the glioma hardly expressed B2 receptor. There were significant differences of bradykinin B2 receptor expression level among different pathological grades of glioma. The expression of B2 receptor in the three grades of glioma was in the order of WHO I < WHO II < WHO III. Determination of bradykinin B2 receptor expression level in human glioma may be useful in screening glioma patients to predict whether they will be suitable for opening of the blood – tumour barrier with bradykinin or its analogue.

Correlation of clinical features and telomerase activity in human gliomas.

Telomerase is a ribonucleoprotein containing an RNA template that synthesizes telomeric DNA. The expression of telomerase activity is concomitant with the attainment of immortality in tumor tissues and cells. In this report, we analyzed telomerase activity in 39 human gliomas with different histological, and in 10 meningiomas, 3 neurinomas, and 2 normal brain tissues by using a polymerase chain reaction (PCR)-based telomeric repeat amplification protocol (TRAP) assay. Telomerase activity was detectable in almost all of the gliomas (36 of 39), but not in any of the meningiomas, neurinomas, or normal brain tissues. In addition, we also analyzed the level of telomerase activity in the 36 gliomas with positive telomerase activity. The relative telomerase activity of the glioma showed a clear association with the pathological grade of glioma; i.e., most of the tumors with high telomerase activity were pathologically of high grade. And also the relative level of telomerase activity could be correlated with the survival time of the patients. These results suggest that the level of telomerase activity in brain tumors is a diagnostic marker indicating the prognosis of the patient as well as the malignant potential of the tumor.