Chunjiang Yu

Migfilin Protein Promotes Migration and Invasion in Human Glioma through Epidermal Growth Factor Receptor-mediated Phospholipase C-γ and STAT3 Protein Signaling Pathways

Background: The oncogenesis and developmental mechanisms of glioma must be clarified to control the disease. Results: Migfilin relates to pathological grades, prognosis of glioma, and regulates motility of glioma cells. Conclusion: Migfilin mediates migration and invasion through EGFR-induced PLC-γ and STAT3 pathways. Significance: Migfilin helps us better understand the pathogenesis of glioma, and Migfilin may be a molecular marker in diagnosis and an indicator in prognosis. Migfilin is critical for cell shape and motile regulation. However, its pathological role in glioma is unknown. Using an immunohistochemical staining assay, we demonstrate that there is a significant correlation between expression of Migfilin and pathological tumor grade in 217 clinical glioma samples. High Migfilin expression is associated with poor prognosis for patients with glioma. Investigation of the molecular mechanism shows that Migfilin promotes migration and invasion in glioma cells. Moreover, Migfilin positively modulates the expression and activity of epidermal growth factor receptor, and Migfilin-mediated migration and invasion depend on epidermal growth factor receptor-induced PLC-γ and STAT3-signaling pathways. Our results may provide significant clinical application, including use of Migfilin as a molecular marker in glioma for early diagnosis and as an indicator of prognosis.

Overexpression of cyclin B1 antagonizes chemotherapeutic-induced apoptosis through PTEN/Akt pathway in human esophageal squamous cell carcinoma cells

The role of cyclin B1 in the clinical therapeutic sensitivity of human esophageal squamous cell carcinoma (ESCC) remains to be defined. In this study, we found that elevated cyclin B1 expression attenuated the apoptosis induced by cisplatin or paclitaxel, while knockdown of cyclin B1 enhanced cisplatin or paclitaxel sensitivity in ESCC cells. Cyclin B1-mediated apoptosis may rely on the Bcl-2-dependent mitochondria-regulated intrinsic death pathway, and the antagonizing effect of cyclin B1 on chemotherapeutic agent-induced apoptosis was through PTEN/Akt pathway. Therefore, cyclin B1 might be a therapeutic target for the development of specific and efficient approaches in the treatment of ESCC.

VCAM-1 siRNA reduces neointimal formation after surgical mechanical injury of the rat carotid artery

OBJECTIVE Restenosis is one of several complications following carotid endarterectomy (CEA). The pathogenesis of restenosis may be related to postsurgery inflammation and leukocyte recruitment mediated by cellular adhesion molecules. In this study, we examine the role of vascular cell adhesion molecule-1 (VCAM-1) in carotid neointimal hyperplasia following carotid surgical mechanical de-endothelialization (CSMDE) in a rat model of CEA. METHODS The inhibition of siRNA on VCAM-1 protein expression was determined by using the methods of immunostaining and Western blot. Ultrasound imaging and morphometric analysis were applied to measure the degree of CSMDE-induced carotid artery neointimal hyperplasia of rats. RESULTS We found that a lentivirus-based construct expressing a small interfering RNA (siRNA) against VCAM-1 could effectively (P < .05, n = 10 per group) reduce VCAM-1 protein expression in the carotid arteries of rats undergoing CSMDE (CSMDE+RNAi: 135.0 +/- 27.6%) when compared that of CSMDE with scrambled siRNA (CSMDE+CON: 182.7 +/- 36.4%). Doppler ultrasonography revealed that CSMDE+RNAi was accompanied by a significant reduction in the extent of stenosis demonstrated by increased blood velocity (665.85 +/- 48.37 mm/s) and linear diameter (0.59 +/- 0.77 mm) compared to CSMDE+CON (46.72 +/- 28.67 mm/s with undetectable linear diameter, P < .05, n = 10 per group). In addition, morphometric analysis of hematoxylin and eosin (HE)-stained sections indicated that the intima (innermost layer of media at lesion site)/media area ratio (I/M) was significantly increased (P < .05, n = 10 per group) both in the CSMDE (3.99 +/- 0.65) and CSMDE+CON (4.33 +/- 0.59) groups compared with the SHAM group (0.35 +/- 0.13). However, CSMDE+RNAi resulted in a significant (P < .05, n = 10 per group) decrease in the I/M ratio (1.79 +/- 0.43) compared to CSMDE+CON, whereas there were no significant differences in the total arterial area and medial areas among the groups. CONCLUSION These results suggest that perivascular events mediated by VCAM-1 are likely to play an important role in the pathogenesis of carotid artery neointimal hyperplasia in rats after CSMDE.

Fluid-fluid level in cystic vestibular schwannoma: a predictor of peritumoral adhesion

OBJECT The aim of this study was to evaluate the clinical results and surgical outcomes of cystic vestibular schwannomas (VSs) with fluid-fluid levels. METHODS Forty-five patients with cystic VSs and 86 with solid VSs were enrolled in the study. The patients in the cystic VSs were further divided into those with and without fluid-fluid levels. The clinical and neuroimaging features, intraoperative findings, and surgical outcomes of the 3 groups were retrospectively compared. RESULTS Peritumoral adhesion was significantly greater in the fluid-level group (70.8%) than in the nonfluid-level group (28.6%) and the solid group (25.6%; p < 0.0001). Complete removal of the VS occurred significantly less in the fluid-level group (45.8%, 11/24) than in the nonfluid-level group (76.2%, 16/21) and the solid group (75.6%, 65/86; p = 0.015). Postoperative facial nerve function in the fluid-level group was less favorable than in the other 2 groups; good/satisfactory facial nerve function 1 year after surgery was noted in 50.0% cases in the fluid-level group compared with 83.3% cases in the nonfluid-level group (p = 0.038). CONCLUSIONS Cystic VSs with fluid-fluid levels more frequently adhered to surrounding neurovascular structures and had a less favorable surgical outcome. A possible mechanism of peritumoral adhesion is intratumoral hemorrhage and consequent inflammatory reactions that lead to destruction of the tumor-nerve barrier. These findings may be useful in predicting surgical outcome and planning surgical strategy preoperatively.

Migfilin sensitizes cisplatin-induced apoptosis in human glioma cells in vitro

Aim:Filamin binding LIM protein 1, also known as migfilin, is a skeleton organization protein that binds to mitogen-inducible gene 2 at cell-extracellular matrix adhesions. The aim of this study was to investigate the role of migfilin in cisplatin-induced apoptosis in human glioma cells, to determine the functional domains of migfilin, and to elucidate the molecular mechanisms underlying the regulation of cisplatin-related chemosensitivity.Methods:The human glioma cell lines Hs683, H4, and U-87 MG were transfected with pEGFP-C2-migfilin to elevate the expression level of migfilin. RNA interference was used to reduce the expression of migfilin. To determine the functional domains of migfilin, U-87 MG cells were transfected with plasmids of migfilin deletion mutants. After treatment with cisplatin (40 μmol/L) for 24 h, the cell viability was assessed using the MTS assay, and the cell apoptotic was examined using the DAPI staining assay and TUNEL analysis. Expression levels of apoptosis-related proteins were detected by Western blot analysis.Results:Overexpression of migfilin significantly enhanced cisplatin-induced apoptosis in Hs683, H4, and U-87 MG cells, whereas downregulation of migfilin expression inhibited the chemosensitivity of these cell lines. The N-terminal region of migfilin alone was able to enhance the cisplatin-induced apoptosis. However, despite the existence of the N-terminal region, mutants of migfilin with any one of three LIM domains deleted led to a function loss. Furthermore, apoptotic proteins (PARP and caspase-3) and the anti-apoptotic protein Bcl-xL were modulated by the expression level of migfilin in combination with cisplatin.Conclusion:The LIM1-3 domains of migfilin play a key role in sensitizing glioma cells to cisplatin-induced apoptosis through regulation of apoptosis-related proteins.

MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation

Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stem-like cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma. In human medulloblastoma, extensive nodularity and large-cell/anaplastic subgroups differed according to the staining levels of MELK and EZH2 from the other two subgroups. The proportion of MELK- or EZH2-positive staining status could be considered as a potential indicator for survival. Mechanistically, MELK bound to and phosphorylated EZH2, and its methylation was induced by EZH2 in medulloblastoma, which could regulate the proliferation of cancer stem-like cells. In xenografts, loss of MELK or EZH2 attenuated medulloblastoma stem-like cell-derived tumor growth and promoted differentiation. These findings indicate that MELK-induced phosphorylation and EZH2-mediated methylation in MELK/EZH2 pathway are essential for medulloblastoma stem-like cell-derived tumor proliferation, thereby identifying a potential therapeutic strategy for these patients. Implications: This study demonstrates that the interaction occurring between MELK and EZH2 promotes self-proliferation and stemness, thus representing an attractive therapeutic target and potential candidate for diagnosis of medulloblastoma. Mol Cancer Res; 15(9); 1275–86. ©2017 AACR.

Localization of transverse-sigmoid sinus junction using preoperative 3D computed tomography: application in retrosigmoid craniotomy.

In retrosigmoid craniotomy, neurosurgeons usually depend on surface landmarks and their experience to evaluate the position of transverse-sigmoid sinus junction (TSSJ) and place an appropriate initial burr-hole, which is not accurate each time because of variability in different craniums. The authors introduce a simple procedure based on 3D computed tomography (CT) to localize the TSSJ in retrosigmoid craniotomy. Eighteen patients who underwent retrosigmoid craniotomy were analyzed. On the internal view of skull in 3D CT image, a simulative burr-hole was placed on the margin of transverse-sigmoid sinus groove junction. Then, on the external view of skull in 3D CT image, the center of the simulative burr-hole was marked and a coordinate system was established based on a line connected the digastric point and the asterion. Then the coordinate of the burr-hole’s center was measured in this coordinate system. In operation, the burr-hole was placed according to the coordinate measured previously and craniotomy was performed. The margin of TSSJ was exposed in each case. No damage of venous sinus was encountered. Post-operative skull base CT demonstrated a good match between the actual and predicted burr-hole and bone defects only existed along the cut line. This simple method could help in localizing the TSSJ and avoiding the risk of sinus injury and reducing the bone defect. It is sufficiently precise for practical application at surgical planning.

Kindlin-2 interacts with β-catenin and YB-1 to enhance EGFR transcription during glioma progression

Kindlin-2 promotes carcinogenesis through regulation of cell-cell and cell-extracellular matrix adhesion. However, the role of Kindlin-2 in glioma has not been elucidated. We investigated Kindlin-2 expression in 188 human glioma tissue samples. High Kindlin-2 expression was correlated with high pathological grade and a worse prognosis. Kindlin-2 promoted glioma cell motility and proliferation both in vitro and in vivo. Importantly, Kindlin-2 activated the EGFR pathway and increased EGFR mRNA levels. In addition to up-regulating Y-box binding protein-1 (YB-1) and β-catenin expression, Kindlin-2 formed a transcriptional complex with YB-1 and β-catenin that bound to the EGFR promoter and enhanced transcription. The β-catenin/YB-1/EGFR pathway was required for Kindlin-2-mediated functions. Our data provide a better understanding of the mechanisms underlying glioma progression, and suggest that Kindlin-2 may be a biomarker and therapeutic target in glioma.

Downregulation of β-arrestin 1 suppresses glioblastoma cell malignant progression vis inhibition of Src signaling

ABSTRACT Glioblastoma multiforme (GBM) is one of the most common brain malignancies worldwide and is typically associated with a dismal prognosis, yet the mechanisms underlying its aggressiveness remain unclear. Here, we revealed that &bgr;‐arrestin 1 was overexpressed in GBM and contributed to poorer outcome. Knockdown of &bgr;‐arrestin 1 suppressed the proliferation, invasiveness and glycolysis of GBM cells, and also enhanced temozolomide efficacy. Further, we discovered that knockdown of &bgr;‐arrestin 1 decreased the activity of Src, and suppression of Src signaling was critically involved in &bgr;‐arrestin 1 silencing‐mediated suppression of GBM malignancies. Finally, we investigated the effect of &bgr;‐arrestin 1 knockdown on the tumor growth and survival of xenograft models, and found that sh&bgr;‐arrestin 1 apparently inhibited GBM growth in vivo and resulted in better survival of mice. Taken together, our findings suggest that knockdown of &bgr;‐arrestin 1 can suppress GBM cell proliferation, invasion and glycolysis by inhibiting Src signaling. Thus, targeting &bgr;‐arrestin 1 may be a potential therapeutic strategy for GBM treatment. HighlightsExpression of &bgr;‐arrestin 1 was upregulated in GBM and contributed to poor outcome.Knockdown of &bgr;‐arrestin 1 inhibited the proliferation and glycolysis of GBM cells.Knockdown of &bgr;‐arrestin 1 decreased the activity of Src signaling and expressions of malignancy‐related factors.Knockdown of &bgr;‐arrestin 1 suppressed GBM growth in vivo.

Sellar and Suprasellar Granular Cell Tumor of Neurohypophysis

IntroductIon Granular cell tumor (GCT) of neurohypophysis was first reported by Boyce and Beadles in 1983.[1] In 2016 WHO classification of central nervous system (CNS) tumors, GCT of neurohypophysis was defined as a distinct diagnosis.[2] Here, we reported two cases of GCT of neurohypophysis misdiagnosed as pituitary adenoma and craniopharyngioma. One of the cases was a very rare fully described neurohypophysial GCT which invaded into the right cavernous sinus [Figure 1a and 1b], indicating that the benign tumor might possess aggressive features.