Yuhui Zhang

Angiocentric glioma with rich blood supply

Angiocentric glioma (AG) was recognized as a distinct clinicopathological tumor in 2007, but it is rarely reported. We report a patient with AG who presented with dizziness, and whose MRI images revealed a circumscribed lesion with heterogeneous contrast enhancement and evidence of previous bleeding. Thirty-three patients with AG have been reported to date. Most AG patients present with intractable seizures, usually in childhood and as young adults. However, the presentations reported are diverse, therefore the final diagnosis of AG should depend on the histopathological examination.

Temozolomide/PLGA microparticles plus vatalanib inhibits tumor growth and angiogenesis in an orthotopic glioma model.

Temozolomide (TM) has anti-tumor activity in patients with malignant glioma. Implantable poly (D,L-lactide-co-glycolide) (PLGA) microparticles of TM (TM-MS) have been developed, enhancing the cytotoxicity of TM to Glioma C6 cells. Vatalanib, as anti-angiogenic agent, has also shown anti-tumor activity with malignant gliomas. We examined the combined effects of TM-MS and vatalanib in a rat orthotopic glioma model and found TM-MS offered a greater tumor inhibition than TM, and combination treatment with both of them improved the survival time versus single agent therapy. The combination treatment also demonstrated an inhibition to rat glioma tumors, a significant decrease in cell proliferation, an increase in apoptosis, and a lower microvessel density within the glioma tumors. The results suggest that TM-MS can more effectively inhibit tumor than TM, and combination treatment with TM-MS and vatalanib inhibits tumor growth and angiogenesis and may prove to be a promising therapy for malignant gliomas.

Long Noncoding RNA miR210HG as a Potential Biomarker for the Diagnosis of Glioma.

Background Glioma remains a diagnostic challenge because of its variable clinical presentation and a lack of reliable screening tools. Long noncoding RNAs (lncRNAs) regulate gene function in a wide range of pathophysiological processes and are therefore emerging biomarkers for prostate cancer, hepatic cancer, and other tumor diseases. However, the effective use of lncRNAs as biomarkers for the diagnosis of glioma remains unproven. Methods This study included 42 glioma patients and 10 healthy controls. lncRNA and mRNA microarray chips were used to identify dysregulated lncRNAs in tumor tissue and tumor-adjacent normal tissue, and SYBR Green–based miRNA quantitative real-time reverse transcription polymerase chain reactions were used to validate upregulated lncRNAs. A receiver operating characteristic curve analysis was conducted to evaluate the diagnostic accuracy of the lncRNA identified as the candidate biomarker. Results miR210HG levels were significantly higher in tumor tissue than in tumor-adjacent normal tissue in participating glioma patients. Serum miR210HG levels were also significantly higher in glioma patients than in healthy controls. The receiver operating characteristic curve showed that serum miR210HG was a specific diagnostic predictor of acute pulmonary embolism with an area under the curve of 0.8323 (95% confidence interval, 0.7347 to 0.9299, p < 0.001). Conclusion Our findings indicate that miR210HG could be an important biomarker for the diagnosis of glioma, and, as such, large-scale investigations are urgently needed to pave the way from basic research to clinical use.

Osteogenic differentiation of bone marrow mesenchymal stem cells by adenovirus-mediated expression of leptin

Previous studies demonstrate that leptin has an osteogenic differentiation effect on bone marrow mesenchymal stem cells (MSCs). However, the effect of adenovirus-mediated leptin on MSCs differentiation has not been reported. To explore the mechanism, we constructed a recombinant adenoviral vector Ad-leptin and transfected propagated MSCs in vitro. The effects of Ad-leptin on MSCs growth and osteogenic differentiation were examined. The results showed that Ad-leptin inhibited the transfected MSCs growth significantly, and up-regulated osteocalcin expression and alkaline phosphatase activity. The expression of Cbfalpha1 and Cbfbeta which were the key factors in osteogenic differentiation was also up-regulated. All the findings suggest that genetic engineering of MSCs to express leptin gene may have potential application in the treatment of several genetic diseases and bone reconstruction.

The association between Salt-inducible kinase 2 (SIK2) and gamma isoform of the regulatory subunit B55 of PP2A (B55gamma) contributes to the survival of glioma cells under glucose depletion through inhibiting the phosphorylation of S6K.

BackgroundPPP2R2C encodes a gamma isoform of the regulatory subunit B55 subfamily consisting PP2A heterotrimeric with A and C subunits. Currently, the precise functions of B55gamma in cancer are still under investigating. In this project, we reported a novel function of B55gamma in the regulation of glucose metabolism in Glioma cells.MethodsWestern blot and immunoprecipitation were performed to determine protein expression and interaction. Cell viability was measured by Typan Blue staining and direct cell counting using hematocytometer. siRNA technology was used to down regulate protein expression.ResultsGlucose uptake and lactate product were suppressed by overexpression of B55gamma in Glioma cells. In addition, cancer cells with larger amount of B55gamma showed higher survival advantages in response to glucose starvation through the dephosphorylation of S6K. From proteomic analysis, we found B55gamma binds with and up regulates SIK2 through the stabilization of SIK2 protein which is required for the B55gamma-mediated suppression of S6K pathway. Knocking down of SIK2 in B55gamma over expressing cells recovered the phosphorylation of S6K.ConclusionIn summary, our project will provide novel insight into the design and development of therapeutic strategies to target the B55gamma-mediated glucose metabolism for the treatment of human brain tumor patients.

Identification of hub genes and regulatory factors of glioblastoma multiforme subgroups by RNA-seq data analysis

Glioblastoma multiforme (GBM) is the most common malignant brain tumor. This study aimed to identify the hub genes and regulatory factors of GBM subgroups by RNA sequencing (RNA-seq) data analysis, in order to explore the possible mechanisms responsbile for the progression of GBM. The dataset RNASeqV2 was downloaded by TCGA-Assembler, containing 169 GBM and 5 normal samples. Gene expression was calculated by the reads per kilobase per million reads measurement, and nor malized with tag count comparison. Following subgroup classification by the non-negative matrix factorization, the differentially expressed genes (DEGs) were screened in 4 GBM subgroups using the method of significance analysis of microarrays. Functional enrichment analysis was performed by DAVID, and the protein-protein interaction (PPI) network was constructed based on the HPRD database. The subgroup-related microRNAs (miRNAs or miRs), transcription factors (TFs) and small molecule drugs were predicted with predefined criteria. A cohort of 19,515 DEGs between the GBM and control samples was screened, which were predominantly enriched in cell cycle- and immunoreaction-related pathways. In the PPI network, lymphocyte cytosolic protein 2 (LCP2), breast cancer 1 (BRCA1), specificity protein 1 (Sp1) and chromodomain-helicase-DNA-binding protein 3 (CHD3) were the hub nodes in subgroups 1–4, respectively. Paired box 5 (PAX5), adipocyte protein 2 (aP2), E2F transcription factor 1 (E2F1) and cAMP-response element-binding protein-1 (CREB1) were the specific TFs in subgroups 1–4, respectively. miR-147b, miR-770-5p, miR-220a and miR-1247 were the particular miRNAs in subgroups 1–4, respectively. Natalizumab was the predicted small molecule drug in subgroup 2. In conclusion, the molecular regulatory mechanisms of GBM pathogenesis were distinct in the different subgroups. Several crucial genes, TFs, miRNAs and small molecules in the different GBM subgroups were identified, which may be used as potential markers. However, further experimental validations may be required.

Overexpression of leptin receptor in human glioblastoma: Correlation with vasculogenic mimicry and poor prognosis

Vasculogenic mimicry (VM) was an important tumor blood supply to complement the endothelial cell-dependent angiogenesis, while leptin and receptor (ObR) involved in angiogenesis in glioblastoma has been reported on previous study, but the relationship between ObR expression and VM formation in human glioblastoma tissues, as well as their prognostic significance still remains unclear. In our study, we found that VM recognized by CD31-/PAS+ immunohistochemical staining in glioblastoma tissues showed a positive correlation with leptin expression (r = 0.58, P < 0.01), as well as ObR expression in glioblastoma tissues (r = 0.61, P < 0.01). Association of glial to mesenchymal transition (GMT)-related molecular with ObR expression and VM formation in glioblastoma tissues indicated that ObR-positive glioblastoma cells with GMT phenotype might be more likely to constitute VM, and co-expression of ObR and CD133 or Nestin to constitute the channel impliated that ObR-positive glioblastoma cells displayed glioblastoma stem cells (GSC) properties. Moreover, Kaplan-Meier statistical analysis showed that patients with more VM or ObR expression displayed poorer prognosis for overall survival times than patients with less expression (VMhigh vs. VMlow: P = 0.033; ObRhigh vs. ObRlow: P = 0.009). And ObR+ glioblastoma cells with GSC characteristic were mostly involved in VM formation, whereas a little part of cells were also related to microvascular density (MVD), which suggested that ObR was an important target for anticancer therapy, so further related studies were needed to improve glioblastoma treatment.Vasculogenic mimicry (VM) was an important tumor blood supply to complement the endothelial cell-dependent angiogenesis, while leptin and receptor (ObR) involved in angiogenesis in glioblastoma has been reported on previous study, but the relationship between ObR expression and VM formation in human glioblastoma tissues, as well as their prognostic significance still remains unclear. In our study, we found that VM recognized by CD31-/PAS+ immunohistochemical staining in glioblastoma tissues showed a positive correlation with leptin expression (r = 0.58, P < 0.01), as well as ObR expression in glioblastoma tissues (r = 0.61, P < 0.01). Association of glial to mesenchymal transition (GMT)-related molecular with ObR expression and VM formation in glioblastoma tissues indicated that ObR-positive glioblastoma cells with GMT phenotype might be more likely to constitute VM, and co-expression of ObR and CD133 or Nestin to constitute the channel impliated that ObR-positive glioblastoma cells displayed glioblastoma stem cells (GSC) properties. Moreover, Kaplan–Meier statistical analysis showed that patients with more VM or ObR expression displayed poorer prognosis for overall survival times than patients with less expression (VMhigh vs. VMlow: P = 0.033; ObRhigh vs. ObRlow: P = 0.009). And ObR+ glioblastoma cells with GSC characteristic were mostly involved in VM formation, whereas a little part of cells were also related to microvascular density (MVD), which suggested that ObR was an important target for anticancer therapy, so further related studies were needed to improve glioblastoma treatment.

Integrated in silico-in vitro characterization, identification and disruption of the intermolecular interaction between SH3 domain-containing protein kinases and human pituitary tumor-transforming gene 1.

The human pituitary tumor-transforming gene-1 (hPTTG1) has been found to be overexpressed in various cancers. Accumulated evidences implicate that some of protein kinases can specifically recognize two PXXP motifs at hPTTG1 C-terminus through their Src homology (SH3) domain and then phosphorylate the protein by their catalytic domain. Here, we integrate in silico analysis and in vitro assay to characterize the intermolecular interaction between the two hPTTG1 motif peptides 161LGPPSPVK168 (M1P) and 168KMPSPPWE175 (M2P) and the SH3 domains of Ser/Thr-specific protein kinases MAP3K and PI3K. It is identified that the two peptides bind to MAP3K SH3 domain with a moderate affinity, but cannot form stable complexes with PI3K SH3 domain. Long time scale molecular dynamics (MD) simulations reveal that the M1P peptide can fold into a standard poly-proline II helix that is bound in the peptide-binding pocket of MAP3K SH3 domain, while the M2P peptide gradually moves out of the pocket during the simulations and finally forms a weak, transient encounter complex with the domain. All these suggest that the MAP3K M1P site is a potential interacting partner of MAP3K SH3 domain, which may mediate the intermolecular recognition between hPTTG1 and MAP3K.