Pin Guo

C-Myc negatively controls the tumor suppressor PTEN by upregulating miR-26a in glioblastoma multiforme cells

The c-Myc oncogene is amplified in many tumor types. It is an important regulator of cell proliferation and has been linked to altered miRNA expression, suggesting that c-Myc-regulated miRNAs might contribute to tumor progression. Although miR-26a has been reported to be upregulated in glioblastoma multiforme (GBM), the mechanism has not been established. We have shown that ectopic expression of miR-26a influenced cell proliferation by targeting PTEN, a tumor suppressor gene that is inactivated in many common malignancies, including GBM. Our findings suggest that c-Myc modulates genes associated with oncogenesis in GBM through deregulation of miRNAs via the c-Myc-miR-26a-PTEN signaling pathway. This may be of clinical relevance.

ID1 affects the efficacy of radiotherapy in glioblastoma through inhibition of DNA repair pathways

Glioblastoma multiforme (GBM) is characterized by poor therapeutic response and poor overall survival. It is crucial that more effective therapies be developed for the treatment of GBM. Inhibitor of DNA binding protein-1 (ID1) has been shown to maintain the self-renewal capacity of neural stem cells and might be involved in the therapeutic resistance of GBM. In the present study, we explored survival data from the The Cancer Genome Atalas database that were based on ID1 expression for patients diagnosed with primary GBMs. Interestingly, patients with high ID1 expression had better survival than patients with low ID1 expression, and a strong correlation was found between radiotherapy efficacy, ID1 expression, and overall survival. We further investigated the relationship between ID1 expression and the radiosensitivity of glioblastoma using glioblastoma cell lines. The clonogenic formation assay showed that U87 ID1-shRNA cells were much less sensitive to radiation. Moreover, both the results of the γH2AX foci staining assay and the comet assay further revealed that ID1 negatively regulates DNA repair processes by downregulating the expression of genes such as DNA ligase IV (LIG4) and ataxia-telangiectasia-mutated. Additionally, ID1 induces G2/M arrest in U87 cells. Taken together, these results suggest that ID1 may be a new prognostic marker for GBM and have important implications for the therapeutic strategies used to treat GBM patients.

Overexpression of isocitrate dehydrogenase-1R132H enhances the proliferation of A172 glioma cells via aerobic glycolysis

Gliomas are the most common type of primary malignancy of the central nervous system. The identification of mutations in the gene encoding isocitrate dehydrogenase‑1 (IDH1) represents a key area of investigation in studies on glioma. The IDH1R132H mutation is a heterozygous point mutation, which affects the amino acid arginine at position 132, however, the metabolic importance of this mutation in tumor cell growth remains to be elucidated. In the present study, A172 glioma cell lines stably overexpressing either wild‑type IDH1 or IDH1R132H were produced. The results demonstrated that the IDH1R132H mutation enhanced the proliferation of the A172 glioma cells in vitro. Furthermore, IDH1R132H performed this function by elevating the expression levels of hypoxia inducible factor‑1α, leading to an increase in the expression levels of the key glycolytic enzymes, glucose transporter 1 and hexokinase 2. Therefore, the metabolism was shifted towards aerobic glycolysis, leading to an increase in glucose uptake and lactate production. These findings demonstrated that the IDH1R132H molecular target was involved in orchestrating the Warburg effect in mutant IDH1R132H glioma cells.

ID1 regulates U87 human cell proliferation and invasion

Despite therapeutic advances, the prognosis of patients diagnosed with malignant glioma has not improved in recent years. In particular, the molecular mechanisms that mediate glioma invasion remain poorly understood. The importance of ID1 in promoting tumor invasion and metastasis has recently emerged and a role for ID1 as a possible molecular marker of tumor aggressiveness has been proposed. To investigate the biological function of ID1 in glioblastomas, ID1-silenced U87 glioblastoma multiforme (GBM) cells were constructed using a small hairpin RNA (shRNA) sequence. The effect of the knockdown of ID1 on proliferation and invasion in these cells was analyzed using the 5-bromo-2′-deoxy-uridine cell proliferation, Transwell invasion, scratch and cell adhesion assays. Compared with the controls, the U87 cells expressing ID1-shRNA exhibited a significantly decreased proliferation and invasion capacity (P<0.05), as well as increased cell adhesion. Furthermore, silencing ID1 reduced the expression of c-Myc, cyclin D1 and β-catenin, while increasing E-cadherin expression in U87 cells. This study showed that ID1 regulates the metastatic potential of GBM cells by controlling the epithelial-mesenchymal transition. Therefore, ID1 is a potential prognostic indicator and therapeutic target in glioblastomas.

Hypoxia/ischemia up-regulates Id2 expression in neuronal cells in vivo and in vitro.

Inhibitor of DNA binding/differentiation 2 (Id2) belongs to a family of transcriptional modulators characterized by a helix-loop-helix (HLH) motif that lacks the basic amino acid domain necessary to bind DNA. The aim of this study was to obtain a better understanding of the role of Id2 in hypoxia/ischemia (H/I)-induced neuronal apoptosis. Following H/I induction in a rat model of middle cerebral artery occlusion (MCAO)/reperfusion, the number of TUNEL-positive cells in cerebral cortices of the penumbra area increased gradually, while the Id2 mRNA and protein expression were also significantly up-regulated. The hypoxia-mimetic, cobalt chloride (CoCl2)-treated rat neuroblastoma B35 cell line also demonstrated enhanced Id2 mRNA and protein expression as well as increased number of cells in the sub-G1 populations after H/I exposure. Consistently, the expression of Bax, a proapoptotic protein, was also up-regulated in vivo and in vitro. Moreover, triple immunofluorescence demonstrated the obvious co-localization of Id2, TUNEL and NeuN in neurons of the penumbra area. These data suggest that H/I up-regulates Id2 expression in neuronal cells, and Id2 might play an important role in H/I-induced neuronal apoptosis.

O-linked mannose β-1,2-N-acetylglucosaminyltransferase 1 correlated with the malignancy in glioma.

AbstractO-linked mannose &bgr;-1,2-N-acetylglucosaminyltransferase 1 (PomGnT1) constitutes one third of the O-linked glycoproteins in brain tissue. However, its functions have been seldom investigated in brain cancers. In this study, immunohistochemistry was used for the detection of the PomGnT1 protein in 133 cases of glioma tissues. Spearman correlation analysis was used for the relationship between PomGnT1 staining and the glioma grade. Receiver operating characteristic curve was used to measure the diagnostic value of PomGnT1 protein in the degree of glioma malignance. We found that PomGnT1 expression was correlated with glioma grade, and it could be used as a marker to distinguish low- and high-grade gliomas. Stably transfected U87 cells were constructed to overexpress short hairpin RNA of PomGnT1. Immunofluorescence test detected that this protein also could restrain the generation of U87 cells’ pseudopodia. Western blotting further showed that the PomGnT1 protein had an impact on the c-myc protein level. In conclusion, our data suggest that PomGnT1 protein was correlated with the malignance of glioma progression, the mechanism involved in glioma cell’s pseudopodium formation, and the expression of c-myc protein.

Early-stage hemangioblastoma presenting as a small lesion with significant edema in the cerebellum.

Hemangioblastomas are benign tumors that are frequently associated with peritumoral cysts; however, their early characteristics before cyst formation remain unclear. In this article, the authors present a novel case of a cerebellar hemangioblastoma presenting as a small solid lesion with significant edema. Surgery was performed to resect the tumor, and a follow-up magnetic resonance imaging scan revealed complete excision of the mass and resolution of the cerebellar edema. Histological examination confirmed that the lesion was a hemangioblastoma. This is the only report in the literature to describe the imaging and histopathologic characteristics of an initial hemangioblastoma in the cerebellum.

Dynamic expression of cerebral cortex and hippocampal glutamate transporters in a rat model of chest compression-induced global cerebral ischemia.

The present study established a rat model of global cerebral ischemia induced by chest compression for six minutes to dynamically observe expressional changes of three glutamate transporters in the cerebral cortex and hippocampus. After 24 hours of ischemia, expression of glutamate transporter-1 significantly decreased in the cerebral cortex and hippocampus, which was accompanied by neuronal necrosis. At 7 days post-ischemia, expression of excitatory amino acid carrier 1 decreased in the hippocampal CA1 region and cortex, and was accompanied by apoptosis. Expression of glutamate-aspartate transporter remained unchanged at 6 hours–7 days after ischemia. These results suggested that glutamate transporter levels were altered at different periods of cerebral ischemia.