Zhijian Yue

Decreased miR-106a inhibits glioma cell glucose uptake and proliferation by targeting SLC2A3 in GBM

BackgroundMiR-106a is frequently down-regulated in various types of human cancer. However the underlying mechanism of miR-106a involved in glioma remains elusive.MethodsThe association of miR-106a with glioma grade and patient survival was analyzed. The biological function and target of miR-106a were determined by bioinformatic analysis and cell experiments (Western blot, luciferase reporter, cell cycle, ntracellular ATP production and glucose uptake assay). Finally, rescue expression of its target SLC2A3 was used to test the role of SLC2A3 in miR-106a-mediated cell glycolysis and proliferation.ResultsHere we showed that miR-106a was a tumor suppressor miRNA was involved in GBM cell glucose uptake and proliferation. Decreased miR-106a in GBM tissues and conferred a poor survival of GBM patients. SLC2A3 was identified as a core target of miR-106a in GBM cells. Inhibition of SLC2A3 by miR-106a attenuated cell proliferation and inhibited glucose uptake. In addition, for each biological process we identified ontology-associated transcripts that significantly correlated with SLC2A3 expression. Finally, the expression of SLC2A3 largely abrogated miR-106a-mediated cell proliferation and glucose uptake in GBM cells.ConclusionsTaken together, miR-106a and SLC2A3 could be potential therapeutic approaches for GBM.

Radiotherapy plus EGFR TKIs in non‐small cell lung cancer patients with brain metastases: an update meta‐analysis

Brain metastasis (BM) is the common complication of non‐small cell lung cancer (NSCLC) with a poor prognosis and dismal survival rate. This update meta‐analysis aimed to derive a more precise estimation of radiotherapy plus epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC patients with BM. PubMed, EMBASE, Web of Science, Google Scholar, and Cochrane Library were searched to identify any relevant publications. After screening the literature and undertaking quality assessment and data extraction, the meta‐analysis was performed using STATA Version 12.0. In total, 15 studies involving 1552 participants were included. The results indicated that radiotherapy plus EGFR TKIs was more effective at improving response rate and disease control rate (DCR) (risk ratio (RR) = 1.48, 95% confidence interval [CI]: 1.12–1.96, P = 0.005; RR = 1.29, 95% CI: 1.02–1.60, P = 0.035; respectively) than radiotherapy alone or plus chemotherapy. Moreover, radiotherapy plus EGFR TKIs significantly prolonged the time to central nervous system progression (CNS‐TTP) (HR = 0.56, 95% CI [0.33, 0.80]; P = 0.000) and median overall survival (OS) (HR = 0.58, 95% CI [0.42, 0.74]; P = 0.000) but significantly increased adverse events (any grade) (RR = 1.25, 95% CI [1.01, 1.57]; P = 0.009), especially rash and dry skin. These results suggested that radiotherapy plus EGFR TKIs produced superior response rate and DCR and markedly prolonged the CNS‐TTP and OS of NSCLC patients with BM. However, combined groups had the higher rate of incidence of overall adverse effects, especially rash and dry skin.

miR‐372 Regulates Glioma Cell Proliferation and Invasion by Directly Targeting PHLPP2

MicroRNAs are known to be involved in carcinogenesis and tumor progression in glioma. Recently, microRNA‐372 (miR‐372) has been proved to play a substantial role in several human cancers, but its functions in glioma remain unclear. In this study, we confirmed that miR‐372 was commonly upregulated in glioma cell lines and tissues. Downregulation of miR‐372 markedly inhibited cell proliferation and invasion and induced G1/S arrest and apoptosis. Consistently, the xenograft mouse model also unveiled the suppressive effects of miR‐372 knockdown on tumor growth. Further studies revealed that miR‐372 modulated the expression of PHLPP2 by directly targeting its 3′‐untranslated region (3′‐UTR) and that miR‐372 expression was inversely correlated with PHLPP2 expression in glioma samples. Silencing of PHLPP2 could rescue the inhibitory effect of miR‐372 inhibitor. Moreover, miR‐372 knockdown suppressed the phosphorylation levels of the major components of PI3K/Akt pathway including Akt, mTOR, and P70S6K. Taken together, our results suggest that miR‐372 functions as an oncogenic miRNA through targeting PHLPP2 in glioma. J. Cell. Biochem. 116: 225–232, 2015.

The histone deacetylase SIRT6 suppresses the expression of the RNA-binding protein PCBP2 in glioma

More than 80% of tumors that occur in the brain are malignant gliomas. The prognosis of glioma patients is still poor, which makes glioma an urgent subject of cancer research. Previous evidence and our present data show that PCBP2 is over-expressed in human glioma tissues and predicts poor outcome. However, the mechanism by which PCBP2 is regulated in glioma remains elusive. We find that SIRT6, one of the NAD(+)-dependent class III deacetylase SIRTUINs, is down-regulated in human glioma tissues and that the level of SIRT6 is negatively correlated with PCBP2 level while H3K9ac enrichment on the promoter of PCBP2 is positively correlated with PCBP2 expression. Furthermore, we identify PCBP2 as a target of SIRT6. We demonstrate that PCBP2 expression is inhibited by SIRT6, which depends upon deacetylating H3K9ac. Finally, our results reveal that SIRT6 inhibits glioma cell proliferation and colony formation in vitro and glioma cell growth in vivo in a PCBP2 dependent manner. In summary, our findings implicate that SIRT6 inhibits PCBP2 expression through deacetylating H3K9ac and SIRT6 acts as a tumor suppressor in human glioma.

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.

Gamma-secretase inhibitor DAPT suppresses glioblastoma growth via uncoupling of tumor vessel density from vessel function

The objective of the current study was to investigate the regulation of VEGF signaling and tumor angiogenesis by gamma-secretase inhibitor DAPT in glioblastoma. Effects of DAPT on VEGFR1, VEGFR2, endothelial cell proliferation and vessel function were evaluated using mouse microvascular endothelial H5V cell line and U87MG xenograft mouse models. We found that DAPT efficiently inhibited Notch signaling, increased VEGFR2 expression, but decreased VEGFR1 expression. DAPT treatment enhanced endothelial cell proliferation when used combined with VEGF, but exerted no effect if used alone. In U87MG xenograft mouse models, DAPT treatment increased tumor vessel density but compromised vessel function, as evidenced by poor perfusion and aggravated hypoxia. Therefore, DAPT treatment results in an uncoupling of tumor vessel density from vessel function and suppresses glioblastoma growth; disturbance of angiogenesis with DAPT presents a novel therapeutic approach for glioblastoma.

Leptin promotes human glioblastoma growth through activating Signal Transducers and Activators of Transcription 3 signaling.

Leptin plays an important role in cancer development and progression. However, its role on human glioblastoma cell line U87 growth and the underlying mechanism remains unexplored. In this study, we assessed the effect of leptin on U87 cells proliferation in vitro and in vivo, elucidating its underlying mechanism. The results showed that leptin significantly promoted U87 tumor cells growth in a time-and-dose-dependent manner. Leptin increased cell DNA synthesis and promoted G(0)/G(1) phase to S phase transition, but without any influence on cell apoptosis. In addition, leptin treatment resulted in phosphorylation of Signal Transducers and Activators of Transcription 3 (STAT3) on Tyr705, the key transcription factor in Janus-Activated Kinase (JAK)/STAT3 signaling pathway. All the data suggest that the JAK/STAT3 signaling pathway may be involved in promoting U87 glioblastoma growth mediated by leptin, which may be a target for anti-neoplastic treatments for glioblastoma.

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.

Leptin enhances the invasive ability of glioma stem-like cells depending on leptin receptor expression.

Glioma stem-like cells have been demonstrated to have highly invasive activity, which is the major cause of glioma recurrence after therapy. Leptin plays a role in glioma invasion, however, whether and how leptin contributes to the biological properties of glioma stem-like cells, such as invasion, remains to be explored. In the current study, we aimed to explore the role of leptin during glioma stem-like cells invasion as well as the signaling pathway. We found that glioma stem-like cells exhibited high invasive potential, especially in the presence of leptin, Ob-R coexpressed with CD133 in glioma stem-like cells was showed to be responsible for leptin mediated invasion of glioma stem-like cells. Our results indicated that leptin served as a key intermediary linking the accumulation of excess adipokine to the invasion of glioma stem-like cells, which may be a novel therapeutic target for suppressing tumor invasion and recurrence.

High expression of leptin receptor leads to temozolomide resistance with exhibiting stem/progenitor cell features in gliobalastoma

Glioblastoma is a highly aggressive malignant disease with notable resistance to chemotherapy. In this study, we found that leptin receptor (ObR)-positive glioblastoma cells were resistant to temozolomide (TMZ), and TMZ-resistant cells exhibited high expression of ObR. ObR can serve as a marker to enrich glioblastoma cells with some stem/progenitor cell traits, which explained the reason for TMZ resistance of ObR+ cells. STAT3-mediated SOX2/OCT4 signaling axis maintained the stem/progenitor cell properties of ObR+ cells, which indirectly regulated glioblastoma TMZ resistance. These findings gain insight into the molecular link between obesity and glioblastoma, and better understanding of this drug-resistant population may lead to the development of more effective therapeutic interventions for glioblastoma.