Glioma Metastasis Research Articles

The Unwanted Cell Migration in the Brain: Glioma Metastasis.

Cell migration is identified as a highly orchestrated process. It is a fundamental and essential phenomenon underlying tissue morphogenesis, wound healing, and immune response. Under dysregulation, it contributes to cancer metastasis. Brain is considered to be the most complex organ in human body containing many types of neural cells with astrocytes playing crucial roles in monitoring both physiological and pathological functions. Astrocytoma originates from astrocytes and its most malignant type is glioblastoma multiforme (WHO Grade IV astrocytoma), which is capable to infiltrate widely into the neighboring brain tissues making a complete resection of tumors impossible. Very recently, we have reviewed the mechanisms for astrocytes in migration. Given the fact that astrocytoma shares many histological features with astrocytes, we therefore attempt to review the mechanisms for glioma cells in migration and compare them to normal astrocytes, hoping to obtain a better insight into the dysregulation of migratory mechanisms contributing to their metastasis in the brain.

Inhibitory effects of microRNA-105 on proliferation and migration of human glioma cells

Objective To investigate the microRNA-105 (miR-105) expression level in brain glioma and the role of miR-105 in the progression and metastasis of brain glioma and assess its value in predicting the prognosis of brain glioma patients. Methods Real-time quantitative polymerase chain reaction (Real-time PCR) was used to detect the expression of miR-105 gene in brain glioma and peri-cancerous tissues. The miR-105 mimic and miR-105 inhibitor were transfected to U87 cells respectively. Cell proliferation was analyzed by cell counting assay kit-8 (CCK-8). Cell invasion assays was analyzed by Transwell assay. Results Real-time PCR showed that the miR-105 expression in human brain glioma tissues was lower than that in non-cancerous brain tissues (6.043±0.427 vs. 5.216±0.418) The expression of miR-105 in brain glioma was reduced to 56.37% of that in peri-cancerous tissues (P=0.000), and was negatively associated to tumor grade (P=0.001). The results of CCK-8 proliferation assay showed that cell proliferation speed was reduced by 0.365±0.033 (50.65%, P=0.002) in miR-105 mimics-transfected cells as compared with that in the untreated cells, and after inhibiting miR-105, the speed was increased by 2.434±0.030 (54.76%, P=0.021). The invasion of the cells that were transfected with the miR-105 mimic was dramatically decreased as compared with the scrambled control and untreated cells (P=0.009). Conclusion miR-105 functions as a tumor suppressor miRNA in brain glioma. The expression of miR-105 is aberrantly low in glioma tissues. Transient transfection of miR-105 mimics leads to decreased proliferation and progression in U87 glioma cells. miR-105 plays an important role in the development of brain glioma. Key words: MicroRNA-105; Glioma; Proliferation; Migration

The value of 1H-MRS in identification of malignant glioma and solitary brain metastases

Objective To investigate the clinical application value of 1H-MRS in identification of malignant glioma and solitary brain metastases. Methods A retrospective study was performed on 24 cases of malignant glioma and 15 cases of solitary brain metastases confirmed by surgery and pathology. All 39 patients underwent conventional MRI, enhanced MR and 1H-MRS imaging. To detect the changes of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr), and achieved ratio of NAA/Cr, Cho/Cr and Cho/NAA in the tumor parenchyma, tumor margin, edema area and contralateral normal brain parenchyma. The ratio of Cho/NAA, Cho/Cr and NAA/Cr in tumor parenchyma area, tumor edge area, edema area and contralateral normal brain parenchyma were compared and analyzed. Results Comparison between the ratio of 1H-MRS metabolite of malignant glioma and solitary brain metastases, in tumor parenchyma, the ratios of NAA/Cr were (0.96±0.42) and (1.66±1.10); in tumor edge area, the ratios of NAA/Cr were (1.07±0.47) and (1.48±0.40), the ratios of Cho/NAA were (2.21±1.20) and (1.21±0.35); in peritumoral edema region, the ratios of NAA/Cr were (1.24±0.62), (1.68±0.35), the ratios of Cho/Cr were (1.78±0.79), (1.10±0.26), the ratios of Cho/NAA were (1.51±0.58), (0.67±0.17), and all the differences were statistically significant (all P<0.05). Conclusion 1H-MRS imaging technology can make up the limitations of conventional MRI.The ratio of 1H-MRS metabolite in peritumoral edema has a significant clinical value in identification of malignant glioma and solitary brain metastases. Key words: Solitary brain metastases; Malignant glioma; Magnetic resonance imaging; Magnetic resonance spectroscopy

CMIP Promotes Proliferation and Metastasis in Human Glioma.

Glioma is one of the most common primary malignant brain tumors and the outcomes are generally poor. The intrinsic mechanisms involved in glioma development and progression remain unclear. Further studies are urgent and necessary. In this study, we have proven that CMIP (C-Maf-inducing protein) promotes cell proliferation and metastasis in A172 cells through knockdown of CMIP and in U251 cells through overexpression of CMIP by using MTT assay, cell colony formation assay, cell migration assay, and cell invasion assay. Furthermore, we discovered that CMIP upregulates MDM2, which is involved in the promoting role of CMIP in human glioma cells. For clinical study, 99 glioma tissues and 59 normal tissues were analyzed. CMIP expression was higher in glioma tissues than in normal tissues. In glioma tissues, CMIP is found to correlate positively with tumor grade but no significant correlation is found with patients' age, gender, or Karnofsky performance score (KPS). Moreover, CMIP also correlates with low relapse-free survival (RFS) rate and overall survival (OS) rate in glioma patients. Therefore, CMIP is oncogenic and could be a potential target for human glioma diagnosis and therapy.

RUNX1 Regulates Migration, Invasion, and Angiogenesis via p38 MAPK Pathway in Human Glioblastoma.

Runt-related transcription factor 1 (RUNX1) is essential for the establishment of fetal and adult hematopoiesis and neuronal development. Aberrant expression of RUNX1 led to proliferation and metastasis of several cancers. The aim of the present study was to investigate the role of RUNX1 in migration, invasion, and angiogenesis of human glioblastoma using IL-1β-treated U-87 MG human glioblastoma cells as a model. IL-1β at 10ng/ml stimulated translocation of RUNX1 into the nucleus with increased expressions of RUNX1, MMP-1, MMP-2, MMP-9, MMP-19, and VEGFA in U-87 MG cells. In addition, silencing of RUNX1 gene significantly suppressed U-87 MG cell migration and invasion abilities. Moreover, knockdown of RUNX1 mRNA in U-87 MG cells reduced the tube formation of human umbilical vein endothelial cells. Further investigation revealed that IL-1β-induced RUNX1 expression might be mediated via the p38 mitogen-activated protein kinase (MAPK) signaling molecule for the expression of these invasion- and angiogenic-related molecules. Together with an inhibitor of p38 MAPK (SB203580) could decrease RUNX1 mRNA expression. Thus, RUNX1 may be one of the putative molecular targeted therapies against glioma metastasis and angiogenesis through the activation of p38 MAPK signaling pathway.

Abstract A050: Cdk5 disruption attenuates tumor PD-L1 expression via regulation of IFN-γ signaling components and promotes antitumor immunity

Abstract In order to escape normal immune surveillance, tumors mimic peripheral tissue tolerance mechanisms such as the expression of programmed cell death-ligand 1 (PD-L1), the inhibition of which can lead to potent anti-tumor responses. Here we show the contribution of cyclin dependent kinase 5 (Cdk5) to immune evasion. Cdk5 is a proline-directed serine/threonine kinase, which is highly expressed in post-mitotic neurons and directs a variety of homeostatic functions from cytoskeletal rearrangement to neurotransmitter signaling. Studies in xenograft models have linked Cdk5 activity to the generation and metabolic activity of primary tumors within the central nervous system (CNS). Here we show that Cdk5, expressed in both murine and human medulloblastoma (MB) cell lines, plays a major role in the ability of MB to avoid immune detection. First, we observed that decreased Cdk5 expression was associated with an increase in the number of infiltrating CD3+ cells in the tumor mass of clinical MB samples. Additionally, using publicly available datasets, we found that decreased Cdk5 expression is correlated with better overall survival or fewer distant metastasis in melanoma, breast cancer, glioma, and lung adenocarcinoma. Next, using a CRISPR/Cas-9 approach, we silenced Cdk5 in a murine model of Sonic Hedgehog (SHH) pathway MB. Rather than causing intrinsic growth defects in MB, interference of Cdk5 activity sensitizes tumors to killing by the normal host immune system in a CD4+ T cell-dependent manner. This rejection is associated with increased IFN-γ expression in the tumor microenvironment, as well as increased PD-L1 expression by myeloid populations in both subcutaneous and intracranial tumors. Mechanistically, we observed an attenuated response to IFN-γ stimulated expression of programmed death ligand 1 (PD-L1) on MB cells. This blunted response was recapitulated when MB cells were treated with Roscovitine, a non-selective Cdk5 inhibitor. Furthermore, using a quantitative global phosphoproteomics approach, we found that Cdk5 knockdown also increased phosphorylation of S-440 and S-443 on interferon regulatory factor binding protein 2 (IRF2BP2), an upstream co-repressor of interferon regulatory factor 2 (IRF-2). Increased phosphorylation of IRF2BP2 corresponded with stable expression of IRF-2 with a concomitant decrease in surface expression of PD-L1. These observations highlight a critical role for Cdk5 in the immune escape mechanisms of primary CNS tumors and provides new therapeutic targets for PD-1/PD-L1 directed immunotherapy. Citation Format: Rodney D. Dorand, Jr., Joseph Nthale, Jay T. Myers, Deborah S. Barkauskas, Stefanie Avril, Steven M. Chirieleison, Tej K. Pareek, Derek W. Abbott, Duncan S. Stearns, John J. Letterio, Alex Y. Huang, Agne Petrosiute. Cdk5 disruption attenuates tumor PD-L1 expression via regulation of IFN-γ signaling components and promotes antitumor immunity [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A050.

The lncRNA H19 interacts with miR-140 to modulate glioma growth by targeting iASPP

H19, one of the first found cancer-associated long non-coding RNAs (lncRNAs), is involved in the development and progression of many types of tumors. An aberrant expression of H19 was observed in hepatocellular carcinoma, cervical cancer, breast cancer, ovarian cancer, and colorectal cancer. However, the exact effects and molecular mechanisms of H19 in glioma progression are still unknown up to now. In this study, we investigated the role of H19 in human glioma cell lines and clinical tumor samples in order to determine the function of this molecule. In our research, lncRNA-H19 was specifically upregulated in glioma cell lines and promoted glioma cell growth through targeting miR-140. Knockdown of H19 inhibited the proliferation and invasion of human glioma cell and suppressed its metastasis in vitro and in vivo. In addition, miR-140 dependent inhibitor of apoptosis-stimulating protein of p53 (iASPP) regulation was required in H19 induced glioma cell growth. These findings indicated that H19 might regulate the tumor growth and metastasis via miR-140 dependent iASPP regulation. Taken together, our data indicated that H19 might be an oncogenic lncRNA that promoted proliferation and metastasis of glioma and could be regarded as a therapeutic target in human glioma.

ARPP-19 promotes proliferation and metastasis of human glioma

Glioma is the most common and aggressive type of human primary brain tumor with a poor outcome. The molecular mechanisms underlying glioma development and progression are still poorly understood. Recent studies have reported a novel role of ARPP-19 in the regulation of cell mitosis and cancer progression. However, no study has been carried out to determine the role of ARPP-19 in human glioma cells and assess the expression and clinical significance of ARPP-19 in human glioma. In this study, we systematically examined the role of ARPP-19 in glioma A172 cells and examined the expression of ARPP-19 and CD147 in 81 cases of human glioma tissue specimens and correlated them to clinicopathological parameters and patient survival. We found that ARPP-19 promoted both proliferation and metastasis of human glioma cells and the expression of ARPP-19 and CD147 in high-grade glioma was significantly higher than that in the low-grade glioma. Patients whose tumors were positive for expression of ARPP-19 or CD147 showed lower relapse-free survival and overall survival than patients whose tumors were negative for ARPP-19 or CD147, respectively. Pearson correlation analysis indicated that there was a statistically significant correlation between ARPP-19 and CD147. Expressions of ARPP-19 and CD147 may serve as biomarkers for high-grade glioma and poor patient survival.

Extraneural Metastasis of High-Grade Gliomas: Systematic Review of Literature and a Discussion of the Roles of Circulating Tumor Cells and Immune System in Gliomagenesis (P6.300)

Extraneural Metastasis of High-Grade Gliomas: Systematic Review of Literature and a Discussion of the Roles of Circulating Tumor Cells and Immune System in Gliomagenesis (P6.300)

Effects of Two Types of Human Cells on Outgrowth of Human Glioma in Rats.

Glioblastoma multiforme (GBM) is one of the malignant brain tumors that occur most frequently. Despite advances in therapy techniques, the cure of GBM is a major concern. Accordingly, there is a lot of interest in devising novel approaches, such as stem cell therapy, to treat patients with GBM. The aim of this study was to investigate the effects of human bone marrow stem (BMS) cells as well as human olfactory ensheathing cells (OECs) on the outgrowth of U87 glioma in rats. OECs and BMS cells were obtained from volunteers. After verification of the stem cell type by flow cytometry and immunocytochemistry (ICC), cells were labeled and injected into human glioma-bearing rats. Magnetic resonance imaging (MRI), Hematoxylin and Eosin (H&E), and Immunohistochemistry (IHC) were utilized to assess the properties of the groups. We found extensive migration and homing of the OECs and BMS cells towards the tumor area. H&E and IHC staining indicated that the grafted OECs survived and prevented the development of glioma. BMS cells supported proliferation and new vessel formation, and metastasis in glioma tissue. OECs and BMS cells can pass the blood brain barrier and reach the glioma mass. Therefore, this approach can be a potentially powerful method for the delivery of therapeutic agents to malignant brain tumors. In addition, these cells may be genetically modified in order to specifically express tumor-suppressive factors.

MicroRNA Regulation of Endothelial Junction Proteins and Clinical Consequence.

Cellular junctions play a critical role in structural connection and signal communication between cells in various tissues. Although there are structural and functional varieties, cellular junctions include tight junctions, adherens junctions, focal adhesion junctions, and tissue specific junctions such as PECAM-1 junctions in endothelial cells (EC), desmosomes in epithelial cells, and hemidesmosomes in EC. Cellular junction dysfunction and deterioration are indicative of clinical diseases. MicroRNAs (miRNA) are ~20 nucleotide, noncoding RNAs that play an important role in posttranscriptional regulation for almost all genes. Unsurprisingly, miRNAs regulate junction protein gene expression and control junction structure integrity. In contrast, abnormal miRNA regulation of junction protein gene expression results in abnormal junction structure, causing related diseases. The major components of tight junctions include zonula occluden-1 (ZO-1), claudin-1, claudin-5, and occludin. The miRNA regulation of ZO-1 has been intensively investigated. ZO-1 and other tight junction proteins such as claudin-5 and occludin were positively regulated by miR-126, miR-107, and miR21 in different models. In contrast, ZO-1, claudin-5, and occludin were negatively regulated by miR-181a, miR-98, and miR150. Abnormal tight junction miRNA regulation accompanies cerebral middle artery ischemia, brain trauma, glioma metastasis, and so forth. The major components of adherens junctions include VE-cadherin, β-catenin, plakoglobin, P120, and vinculin. VE-cadherin and β-catenin were regulated by miR-9, miR-99b, miR-181a, and so forth. These regulations directly affect VE-cadherin-β-catenin complex stability and further affect embryo and tumor angiogenesis, vascular development, and so forth. miR-155 and miR-126 have been shown to regulate PECAM-1 and affect neutrophil rolling and EC junction integrity. In focal adhesion junctions, the major components are integrin β4, paxillin, and focal adhesion kinase (FAK). Integrin β4 has been regulated by miR-184, miR-205, and miR-9. Paxillin has been regulated by miR-137, miR-145, and miR-218 in different models. FAK has been regulated by miR-7, miR-138, and miR-135. Deregulation of miRNAs is caused by viral infections, tumorigenesis, and so forth. By regulation of posttranscription, miRNAs manipulate junction protein expression in all cellular processes and further determine cellular fate and development. Elucidation of these regulatory mechanisms will become a new alternative therapy for many diseases, such as cancers and inflammatory diseases.

Role of KIF2A in the progression and metastasis of human glioma.

KIF2A is a member of the kinesin-13 family and is involved in cell mitosis and spindle assembly. The abnormal expression and dysfunction of KIF2A are associated with tumorigenesis and the progression of certain human cancer types; however, little is known about the expression and roles of KIF2A in glioma. In the present study, the expression of KIF2A in 35 freshly isolated human glioma tissue samples was analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). The association between the expression of KIF2A and clinicopathological parameters were assessed using the χ(2) test. The biological functions of KIF2A on the proliferation, apoptosis, migration and invasion of glioma cells were investigated using an A172 cell line. RT-qPCR and IHC results demonstrated that the mRNA and protein expression levels of KIF2A were significantly higher in grade III-IV glioma tissues compared with those in grade I-II glioma tissues (P<0.05). No significant correlation was observed between the expression of KIF2A, and age, gender, tumor location and size (P>0.05). In vitro, KIF2A gene silencing inhibited the proliferation, migration and invasion, and induced apoptosis in cancer cells. The present data suggested that KIF2A may be important in glioma progression and may serve as a novel predictive factor and therapeutic target for glioma.

PCSM-04A PROSPECTIVE MULTICENTER SINGLE-ARM CLINICAL TRIAL OF BEVACIZUMAB FOR PATIENTS WITH SURGICALLY UNTREATABLE SYMPTOMATIC BRAIN RADIATION NECROSIS

PURPOSE: Brain radiation necrosis (BRN) is a serious adverse event of radiotherapy especially for malignant brain tumors such as glioma and cancer metastasis, which can deteriorate the quality of life in the patients. Since vascular endothelial growth factor is a forcible vascular permeability factor highly expressed in BRN, bevacizumab is expected be an alternative treatment to reduce its perilesional edema. We performed a prospective, multicenter, single-arm trial involving patients with symptomatic BRN to evaluate the safety and efficacy of bevacizumab. PATIENTS AND METHODS: Patients with surgically untreatable symptomatic BRN refractory to conventional treatments (e.g. corticosteroid, anti-coagulants, or hyperbaric oxygen therapy) were enrolled. We judged that a major cause of perilisional edema was BRN, not tumor recurrence, when lesion/normal brain ratio showed ≤ 1.8 or ≤ 2.5 on 11C-methionine and 18 F-boronophenylalanine positron emission tomography (PET), respectively. 5mg/kg of bevacizumab was administrated 6 cycles biweekly. ≥30% reduction of perilesional edema lasting at least one month was specified as the primary endpoint. RESULTS: Forty-one patients were enrolled in this trial. The primary endpoint was achieved in 30 out of 38 (78.9%) patients at 3.03 months (median) after enrollment. Sixteen patients (42.1%) experienced improvement of Karnofsky performance status. Corticosteroid could be reduced in 29 patients (76.3%). Adverse events with grade ≥3 occurred in 10 patients (24.4%). CONCLUSION: Bevacizumab treatment offers certain clinical benefits for patients with surgically untreatable symptomatic BRN. The determination using amino acid PET, not biopsy, is valid and less invasive for eligibility to administrate bevacizumab.

P56: Molecular chaperones Hdj1, Hdj2 and Hsp70 in model glioma metastasis progression

Glioblastoma is one of the most malignant cancer types. Its median survival is 15 months with combined radio- and chemotherapy and only 4 months without therapy. Molecular chaperones play a very multifaced role in tumor development. Depletion of Hdj1 in cancer cells accelerates tumor growth. Decrease of Hdj2 level correlates with the increase of tumor aggressiveness, but also attenuates tumor protection against radiotherapy. Hsp70 provides considerable survival advantages to the cancer cells, but at the same time can act as a “chaperokine”, activating antitumoral immunity. For assessment of chaperone’s role in glioma progression, invasiveness and metastasis formation we chose rat model of intracranial injection of 10 5 C6 cells. We developed three C6-based cell lines with protein knock-down by RNA-interference: C6 shHsp70 (on 83%), C6 shHdj1 (on 96%) and C6 shHdj2 (on 52%). The last differed in roundish and easily detachable morphology. Following intracranial injection of the modified tumor cells, the animals’ survival was estimated. As compared to the groups of control C6 (25.4 ± 3.9 days) and C6 shHdj1 (25.5 ± 3.8) we observed a nearly 1.5-fold decrease in survival in C6 shHdj2 (16.8 ± 3.5 days) ( P Our experiments proved the high importance of Hdj2 level in glioma progression, invasion and metastasis.

Expression and mutation analysis of Cyclin A and Ki-67 in glioma and their correlation with tumor progression.

The present study aimed to analyze the expression and mutation of Cyclin A and Ki-67 in gliomas, and determine their correlation with tumor progression. Tissue samples of 186 diagnosed glioma patients were examined immunohistochemically for Cyclin A and Ki-67 expression. Gene mutation analysis was performed on genomic DNA extracted from patient samples, using polymerase chain reaction amplification and sequencing. Cyclin A and Ki-67 expression were observed in the glioma and lymphatic metastasis tissues, and were analyzed using SPSS 14.0 statistical software. Of the total patients, 64 (34.41%) were Cyclin A-positive and 68 (36.56%) were Ki-67-positive. The expression of Cyclin A and Ki-67 in glioma was positively correlated with lymphatic metastasis. Statistically significant differences were observed in the mutation rate of Ki-67 (P<0.05), but not Cyclin A (P>0.05), between the gliomas and metastatic tumors. In conclusion, Cyclin A and Ki-67 are highly expressed in glioma tissues, and their expression and mutation are associated with the lymphatic metastasis of glioma in the brain. It may be concluded that Cyclin A and Ki-67 may be used as biomarkers to guide the diagnosis of glioma and evaluate the prognosis of affected patients.

The influence of SRPK1 on glioma apoptosis, metastasis, and angiogenesis through the PI3K/Akt signaling pathway under normoxia.

Gliomas, the most common primary brain tumors, have low survival rates and poorly defined molecular mechanisms to target for treatment. Serine/arginine SR protein kinases 1 (SRPK1) can highly and specifically phosphorylate the SR protein found in many tumors, which can influence cell proliferation and angiogenesis. However, the roles and regulatory mechanisms of SRPK1 in gliomas are not understood. The aim of this study was to determine the functions and regulation of SRPK1 in gliomas. We found that SRPK1 inhibition induces early apoptosis and significantly inhibits xenograft tumor growth. Our results indicate that SRPK1 affects Akt and eIF4E phosphorylation, Bax and Bcl-2 activation, and HIF-1 and VEGF production in glioma cells. Moreover, transfection of SRPK1 siRNA strongly reduced cell invasion and migration by regulating the expression of MMP2 and MMP9 and significantly decreased the volume of tumors and angiogenesis. We show here that a strong link exists among SRPK1, Akt, eIF4E, HIF-1, and VEGF activity that is functionally involved in apoptosis, metastasis, and angiogenesis of gliomas under normoxic conditions. Thus, SRPK1 may be a potential anticancer target to inhibit glioma progression.

SOX9 Overexpression Promotes Glioma Metastasis via Wnt/β-Catenin Signaling.

SOX9 gene encodes a transcription factor essential for a central role in the development and differentiation of multiple cell lineages, such as in neurogenesis, neural crest development, etc. Recent study reported that overexpression of SOX9 mRNA is closely associated with poor clinical outcome of patients with malignant gliomas. In the present study, we have explored the regulatory role of SOX9 in glioma metastasis. To investigate the role of SOX9 in glioma metastasis, SOX9 overexpressed in human glioma cell line U251 on cell migration and invasion was evaluated via wound scratch, Transwell assay without or with Matrigel. SOX9-induced changes in EMT process were evaluated by Western blot. Furthermore, the role of β-catenin in the regulatory effect of SOX9 on cell migration and invasion, and EMT process was explored by suppressing β-catenin expression in SOX9-overexpressed U251 cells. SOX9 overexpression in U251 cells resulted in a significant increase in cell migration and invasion. SOX9 overexpression also markedly promoted the EMT process. More importantly, our results revealed that SOX9 stimulated metastasis through activating Wnt/β-catenin signaling. In summary, this study indicated that the promoting effect of SOX9 on glioma metastasis was, at least in part, through Wnt/β-catenin signaling. The findings in this study highlight the effectiveness and therapeutic potential to utilize SOX9 targeted strategies in the treatment of glioma.

MicroRNA-27b inhibits Spry2 expression and promotes cell invasion in glioma U251 cells.

MicroRNA (miR)-27b has been reported to participate in glioma. However, a detailed role of miR-27b and the underlying mechanism remain largely unknown. The present study found that the expression of miR-27b was significantly increased in glioma tissues compared with normal adjacent tissues. In addition, miR-27b was also upregulated in the U87, U251 and SHG44 glioma cell lines compared with normal human astrocytes. Sprouty homolog 2 (Spry2), which has been reported to be associated with invasive glioma, was identified as a novel target of miR-27b in U251 glioma cells, and the protein expression of Spry2 was negatively regulated by miR-27b in U251 cells. Additionally, inhibition of miR-27b and upregulation of Spry2 suppressed glioma cell invasion, while downregulation of Spry2 reversed the suppressive effect of miR-27b inhibition on glioma cell invasion. These data suggest that miR-27b may promote glioma cell invasion through direct inhibition of Spry2 expression. The data also suggest that miR-27b may become a promising molecular target for inhibiting the invasion and metastasis of glioma.

CXCL12 G801A polymorphism and susceptibility to glioma: a case‑control study.

Previous studies have demonstrated that the CXCL12 G801A polymorphism is closely correlated with tumor susceptibility. In addition, the CXCL12/CXCR4 pathway is closely related to proliferation, metastasis, and invasion of glioma. However, the genetic effects of the CXCL12 G801A polymorphism on glioma risk in Chinese populations remain unknown. In this study, we investigated the potential associations between the CXCL12 G801A polymorphism with glioma susceptibility and its clinicopathological characteristics. Frequencies of CXCL12 G801A polymorphic variants between glioma patients (N = 750) and healthy controls (N = 750) were assessed using restriction length fragment polymorphism analysis. The association among the CXCL12 G801A polymorphism, glioma grade (WHO classification), and histological type was also evaluated. Our results showed that patients with glioma had significantly higher frequency of the CXCL12-3' A/A genotypes (P = 0.039) as compared with healthy controls. When stratified by the glioma histology, high-grade glioma patients had significantly higher frequency of the CXCL12-3' A/A genotypes (P = 0.019) as compared with low-grade glioma patients. When stratified by the WHO grade, significantly higher frequency of the CXCL12-3' A/A genotype was observed in stage IV glioma patients (P = 0.037). We conclude that the CXCL12 G801A polymorphism is a risk factor that increases susceptibility to gliomas in a subset of the general Han Chinese population.

MiR-451 suppresses cell proliferation and metastasis in A549 lung cancer cells.

Recent study showed that inflammation was related to lung cancer. However, the exact cause of lung inflammation leading to carcinogenesis is unknown. MicroRNAs (miRNAs) are a group of endogenous non-coding small RNAs that regulate the activity of targeted mRNAs by inflammatory response in many diseases. MiR-451 was reported to relate to the development of lung cancer and metastasis of glioma. But the effect of miR-451 on cell proliferation, migration, and invasion of lung cancer is not really clear. In order to explore the molecular mechanism of the occurrence and development of lung cancer, we investigated the effect of human miR-451 on the proliferation, invasion, and metastasis in lung cancer cell line A549. The miR-451 expression construct was generated into pGenesil-1.1 and transfected into A549 cells. Results showed that the recombinant vectors were verified by sequencing. And miR-451 was over-expressed in A549 by real-time RT PCR. Furthermore, the proliferation, invasion, and metastasis of the cells in miR-451 group were inhibited significantly compared with those in control and A549 groups by MTT assay, Transwell invasion assay, and wound-healing assay. And the lung cancer metastasis factors (MMP-2, MMP-9, VEGF, and CXCR4) were decreased in miR-451 group by Western blot. Moreover, it was proved that inflammation-related gene-PSMB8 was a target for miR-451 by bioinformatics analysis and dual-luciferase reporter assay. And the protein expressions of PSMB8 and NOS2 were decreased in miR-451 group compared with those in control and A549 groups. Therefore, our findings indicated that miR-451 related to PSMB8/NOS2 inflammatory factors may suppress the development and migration of lung cancer, providing evidence for the role of miR-451 in lung cancer.