Laixing Wang

Avoidance and management of surgical and hardware-related complications of deep brain stimulation.

Objective: Although deep brain stimulation (DBS) is nonablative, it may give rise to many complications. In order to identify and reduce factors contributing to the complications, we performed a retrospective analysis of patients who received DBS in our institution over a 9-year period from March 2000 to December 2008. Methods: Included in this study were 161 patients (85 male and 76 female). Data from these patients were collected and analyzed with respect to the complications and factors potentially related to these complications. Results: A total of 25 surgical and hardware-related complications occurred in 24 patients, including confusion in 11 cases (6.83%), asymptomatic intracranial hemorrhage in 1 case (0.62%), electrode misplacement in 2 cases (1.24%), infection of the subcutaneous pocket receiving the pulse generator in 1 case (0.62%), skin erosion in 2 cases (1.24%), pulse generator seroma formation in 6 cases (3.72%), and device malfunction in 1 case (0.62%). There was no permanent neurological deficit. Conclusion: Confusion is the most common complication in simultaneous bilateral DBS targeting the subthalamic nucleus, especially in patients with severe Parkinson’s disease. With increasing experience of surgeons, complete obedience to intraoperative surgical routines and reasonable application of the microelectrode recording technique, other complications could also be reduced.

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.

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.

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.

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.

Five-year follow-up of 23 asymmetrical Parkinson's disease patients treated with unilateral subthalamic nucleus stimulation

In this study, 23 asymmetrical Parkinsons disease patients were treated with unilateral deep brain stimulation of the subthalamic nucleus and followed up for 5 years. At 5 years after stimulation treatment, Unified Parkinsons Disease Rating Scale II, III and axial symptom scores in the off-drug condition were significantly increased compared those at baseline. However, total Unified Parkinsons Disease Rating Scale II, III and axial symptom scores were significantly lower with stimulation-on compared with the synchronous stimulation-off state in off-drug condition, and the motor symptoms of contralateral side limbs were effectively controlled. Only low Hoehn-Yahr stage was correlated with good long-term postoperative improvement in motor symptoms. The mean levodopa-equivalent daily dose after stimulation treatment was significantly lower than that before treatment, but dyskinesias became worse. Our experimental findings indicate that unilateral deep brain stimulation of the subthalamic nucleus is an effective treatment for improving motor symptoms in well selected asymmetrical Parkinsons disease patients presenting no severe axial symptoms and dyskinesias.