EphA2 is a functional entry receptor for HCMV infection of glioblastoma cells.

Human cytomegalovirus (HCMV) infection is associated with human glioblastoma, the most common and aggressive primary brain tumor, but the underlying infection mechanism has not been fully demonstrated. Here, we show that EphA2 was upregulated in glioblastoma and correlated with the poor prognosis of the patients. EphA2 silencing inhibits, whereas overexpression promotes HCMV infection, establishing EphA2 as a crucial cell factor for HCMV infection of glioblastoma cells. Mechanistically, EphA2 binds to HCMV gH/gL complex to mediate membrane fusion. Importantly, the HCMV infection was inhibited by the treatment of inhibitor or antibody targeting EphA2 in glioblastoma cells. Furthermore, HCMV infection was also impaired in optimal glioblastoma organoids by EphA2 inhibitor. Taken together, we propose EphA2 as a crucial cell factor for HCMV infection in glioblastoma cells and a potential target for intervention.

Poor Karnofsky performance status is not a contraindication for neurosurgical resection in patients with lung cancer brain metastases: a multicenter, retrospective PSM-IPTW cohort study.

BACKGOUND: Neurosurgical resection is a standard local treatment for lung cancer brain metastases (BMs). This study aims to investigate whether neurosurgical resection provides survival benefit in lung cancer BMs with poor KPS. MATERIALS AND METHODS: This multicenter retrospective study included 386 lung cancer BMs with pretreatment KPS ≤ 70 among a total of 1177 lung cancer BMs treated at three centers from August 2010 to July 2021. Data analysis was performed from July to September 2022. Inverse probability of treatment weighting (IPTW) and propensity scores matching (PSM) based on propensity scoring were used to minimize bias. The main outcome was overall survival (OS) after diagnosis of BMs. Risk factors of OS were estimated using Cox proportional hazards regression models. All Characteristics were included in the multivariate Cox regression. RESULTS: 386 patients with pretreatment KPS ≤ 70 were included (age mean [SD], 57.85 [10.36] years; KPS mean [SD], 60.91 [10.11]). Among them, 111 patients received neurosurgical resection, while 275 patients did not. Baseline characteristics were balanced between groups after IPTW or PSM. Neurosurgical resection was associated with significantly better prognosis in unadjusted multivariate COX analysis (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: 0.51-0.91, P = 0.01), and PSM-adjusted multivariate COX analysis (HR: 0.61, 95%CI: 0.39-0.94, P = 0.03), IPTW-adjusted multivariate COX analysis (HR: 0.58, 95%CI: 0.40-0.84, P = 0.004). OS was significantly longer in neurosurgical resection group compared with non-surgical resection group according to unadjusted data (Median OS, surgery vs non-surgery, 14.7 vs 12.5 months, P = 0.01), PSM-adjusted data (median OS, 17.7 vs 12.3 months, P < 0.01) and IPTW-adjusted data (median OS, 17.7 vs 12.5 months, P < 0.01). CONCLUSIONS: Neurosurgical resection was associated with improved survival in patients with lung cancer BMs with poor KPS, suggesting that poor KPS is not a contraindication for neurosurgical resection in these patients.

Survival Benefit from Surgical Resection in Lung Cancer Patients with Brain Metastases: a Single-Center, Propensity-Matched Analysis Cohort Study.

BACKGROUND: Brain metastases (BMs) are the most serious complication of lung cancer, affecting the prognosis of lung cancer patients, and pose distinct clinical challenges. This study was designed to explore the prognostic factors related to lung cancer BM and the value of surgical resection in BMs from lung cancer. METHODS: A retrospective analysis was performed on 714 patients with lung cancer BMs screened between January 2010 and January 2018 at the Sun Yat-sen University Cancer Center. A 1:1 propensity score matching analysis was performed to reduce the potential bias between the surgery and the nonsurgery group. In both the raw and the propensity-score matched dataset, univariate and multivariate Cox proportional hazards regression analyses were used to evaluate risk factors for survival. RESULTS: After matching, 258 patients (129 surgery, 129 no surgery) were analyzed. Multivariate analyses after propensity score matching demonstrated that surgical resection was an independent protective factor for overall survival (OS), and older age, lower Karnofsky Performance Scale (KPS) score, and extracranial metastases were independent risk factors for worse OS. Patients without extracranial metastases, without synchronous BM and with a single BM had a better prognosis. CONCLUSIONS: The findings showed that surgical resection, age, KPS score, and extracranial metastases are independent prognostic factors for predicting the OS of patients with lung cancer BMs, and surgical resection for brain metastatic lesions could significantly improve the OS. However, only certain groups of patients with BMs can benefit from intracranial lesion resection, such as no extracranial metastases and metachronous metastases.

Establishment of Human Pituitary Neuroendocrine Tumor Derived Organoid and Its Pilot Application for Drug Screening.

CONTEXT: Precision medicine for pituitary neuroendocrine tumors (PitNETs) is limited by the lack of reliable research models. OBJECTIVE: To generate patient-derived organoids (PDOs), which could serve as a platform for personalized drug screening for PitNET patients. DESIGN: From July 2019 to May 2022, a total of 32 human PitNET specimens were collected for the establishment of organoids with an optimized culture protocol. SETTING: This study was conducted at Sun Yat-Sen University Cancer Center. PATIENTS: PitNET patients who were pathologically confirmed were enrolled in this study. INTERVENTIONS: Histological staining and whole-exome sequencing were utilized to confirm the pathologic and genomic features of PDOs. A drug response assay on PDOs was also performed. MAIN OUTCOME MEASURES: PDOs retained key genetic and morphological features of their parental tumors. RESULTS: PDOs were successfully established from various types of PitNET samples with an overall success rate of 87.5%. Clinical nonfunctioning PitNETs-derived organoids (22/23, 95.7%) showed a higher likelihood of successful generation compared to those from functioning PitNETs (6/9, 66.7%). Preservation of cellular structure, subtype-specific neuroendocrine profiles, mutational features, and tumor microenvironment heterogeneity from parental tumors was observed. A distinctive response profile in drug tests was observed among the organoids from patients with different subtypes of PitNETs. With the validation of key characteristics from parental tumors in histological, genomic, and microenvironment heterogeneity consistency assays, we demonstrated the predictive value of the PDOs in testing individual drugs. CONCLUSION: The established PDOs, retaining typical features of parental tumors, indicate a translational significance in innovating personalized treatment for refractory PitNETs.

Cerebrospinal fluid protein levels are elevated 100 times in a Leptomeningeal metastasis patient: a case report and literature review.

Leptomeningeal metastasis (LM) has a high degree of malignancy and high mortality. We describe a patient admitted to hospital with acute lower extremity weakness, dysuria, and high intracranial pressure. Enhanced magnetic resonance imaging (MRI) showed extensive enhancement of the leptomeningeal and spinal meninges with multiple nodular changes and extensive fusion. His cerebrospinal fluid (CSF) was yellow and cloudy, the Pandy test was strongly positive (++++), the protein was 46 g/L (normal range 0.15-0.45 g/L), which attracted our attention. Initially, miliary TB with associated tuberculous meningitis (TBM) was diagnosed, and neurosarcoidosis cannot be ruled out. After poor therapeutic effect of standard antituberculosis (anti-TB) therapy, further inspection found that malignant cells were detected by cerebrospinal fluid (CSF) cytology. PET/CT suggested the diagnosis of LM. The purpose of this paper is to describe the characteristics of atypical diffuse LM. In conclusion, when patient with unexplained high levels of CSF protein, it is necessary to be alert to the diagnosis of LM. Multiple examinations of fresh CSF are helpful to increase the positive detection rate of tumor cells. Early diagnosis and active treatment are conducive to improving survival rate.

Survival Benefits of Radiotherapy and Surgery in Lung Cancer Brain Metastases with Poor Prognosis Factors.

BACKGROUND: Radiotherapy and surgery are the standard local treatments for lung cancer brain metastases (BMs). However, limited studies focused on the effects of radiotherapy and surgery in lung cancer BMs with poor prognosis factors. METHODS: We retrospectively analyzed 714 patients with lung cancer BMs. Analyses of overall survival (OS) and risk factors for OS were assessed by the log-rank test and Cox proportional hazard model. RESULTS: Age ≥ 65 years, a Karnofsky Performance Scale (KPS) score ≤ 70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, and extracranial metastases were related to poor prognosis. Patients were stratified according to these poor prognosis factors. In patients with the ALK/EGFR wild type, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and surgery improved the OS of patients. WBRT and SRS were the independent protective factors for OS. In patients with extracranial metastases, patients who received WBRT plus SRS or WBRT alone had longer OS than those who did not receive radiotherapy. WBRT plus SRS and WBRT were the independent protective factors for OS. CONCLUSIONS: Radiotherapy and surgery are associated with improved survival for lung cancer BMs with the ALK/EGFR wild type. Radiotherapy is associated with improved survival in lung cancer BMs with extracranial metastases.

Analysis of the potential role of photocurable hydrogel in patient-derived glioblastoma organoid culture through RNA sequencing.

Patient-derived glioblastoma organoid (GBO) growth in hydrogels recapitulates key features of parental tumors, making GBOs a useful tool for fundamental research on cancer biology and offer deeper insight into the development of innovative therapeutic strategies for cancer treatment. Matrigel as a natural hydrogel has been widely used for 3D culture in most tumor organoid studies, but the volatility in its biochemical and biophysical properties makes it difficult to be further applied in GBO cultures. Thus, several kinds of biomimetic hydrogels from synthetic or biological polymers have been developed for tumor organoid growth. Here, we innovatively utilize a photocurable hydrogel-based biomimetic instructive system containing gelatin methacryloyl (GelMA) mixed with a hyaluronic acid (HA) hydrogel as a scaffold for generating GBOs. Furthermore, we evaluated the GBO biological properties at the transcriptome level, which showed that GBOs cultured with this hydrogel retain the expression profile of key neurodevelopmental markers, driving mutations and alternative splicing of parental tumors. Notably, GBOs cultured with the photocurable hydrogel may provide a platform for precision cancer medicine, bridging the gap between basic research and clinical application. Although significant challenges remain, biomimetic hydrogels can provide an exceptional window for the construction of tumor organoids to ensure the accuracy of the research and clinical data.

In Situ Sprayed Starvation/Chemodynamic Therapeutic Gel for Post-Surgical Treatment of IDH1 (R132H) Glioma.

Complete resection of isocitrate dehydrogenase 1 (IDH1) (R132H) glioma is unfeasible and the classic post-surgical chemo/radiotherapy suffers from high recurrence and low survival rate. IDH1 (R132H) cells are sensitive to low concentrations of glucose and high concentrations of reactive oxygen species (ROS) due to inherent metabolism reprograming. Hence, a starvation/chemodynamic therapeutic gel is developed to combat residual IDH1 (R132H) tumor cells after surgery. Briefly, glucose oxidase (GOx) is mineralized with manganese-doped calcium phosphate to form GOx@MnCaP nanoparticles, which are encapsulated into the fibrin gel (GOx@MnCaP@fibrin). After spraying gel in the surgical cavity, GOx catalyzes the oxidation of glucose in residual IDH1 (R132H) cells and produces H2 O2 . The generated H2 O2 is further converted into highly lethal hydroxyl radicals (•OH) by a Mn2+ -mediated Fenton-like reaction to further kill the residual IDH1 (R132H) cells. The as-prepared starvation/chemodynamic therapeutic gel shows much higher therapeutic efficacy toward IDH1 (R132H) cells than IDH1 (WT) cells, and achieves long-term survival.

Immunogenomic Profiling Demonstrate AC003092.1 as an Immune-Related eRNA in Glioblastoma Multiforme.

Enhancer RNAs, a type of long non-coding RNAs (lncRNAs), play a critical role in the occurrence and development of glioma. RNA-seq data from 161 glioblastoma multiforme (GBM) samples were acquired from The Cancer Genome Atlas database. Then, 70 eRNAs were identified as prognosis-related genes, which had significant relations with overall survival (log-rank test, p < 0.05). AC003092.1 was demonstrated as an immune-related eRNA by functional enrichment analysis. We divided samples into two groups based on AC003092.1 expression: AC003092.1 High (AC003092.1_H) and AC003092.1 Low (AC003092.1_L) and systematically analyzed the influence of AC003092.1 on the immune microenvironment by single-sample gene-set enrichment analysis and CIBERSORTx. We quantified AC003092.1 and TFPI2 levels in 11 high-grade gliomas, 5 low-grade gliomas, and 7 GBM cell lines. Our study indicates that AC003092.1 is related to glioma-immunosuppressive microenvironment, and these results offer innovative sights into GBM immune therapy.

Glucose Oxidase-Instructed Traceable Self-Oxygenation/Hyperthermia Dually Enhanced Cancer Starvation Therapy.

Cancer theranostics based on glucose oxidase (GOx)-induced starvation therapy has got more and more attention in cancer management. Herein, GOx armed manganese dioxide nanosheets (denoted as MNS-GOx) were developed as cancer nanotheranostic agent for magnetic resonance (MR)/photoacoustic (PA) dual-modal imaging guided self-oxygenation/hyperthermia dually enhanced starvation cancer therapy. The manganese dioxide nanomaterials with different morphologies (such as nanoflowers, nanosheets and nanowires) were synthesized by a biomimetic approach using melanin as a biotemplate. Afterwards, the manganese dioxide nanosheets (MNS) with two sides and large surface area were selected as the vehicle to carry and deliver GOx. The as-prepared MNS-GOx can perform the circular reaction of glucose oxidation and H2O2 decomposition for enhanced starvation therapy. Moreover, the catalytic activity of GOx could be further improved by the hyperthermia of MNS-GOx upon near-infrared laser irradiation. Most intriguingly, MNS-GOx could achieve "turn-on" MR imaging and "turn-off" PA imaging simultaneously. The theranostic capability of MNS-GOx was evaluated on A375 tumor-bearing mice with all tumor elimination. Our findings integrated molecular imaging and starvation-based synergistic cancer therapy, which provided a new platform for cancer nanotheranostics.

miR-504 suppresses mesenchymal phenotype of glioblastoma by directly targeting the FZD7-mediated Wnt-ß-catenin pathway.

BACKGROUND: MicroRNAs (miRNAs) play crucial roles in tumor initiation and development. Previously, we indicated that miR-504 is downregulated and suppresses tumor proliferation in glioblastoma (GBM). However, the regulation and relevant mechanism of miR-504 in GBM mesenchymal (ME) transition remain unclear. METHODS: Transcriptome and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. The potential functions of miR-504 were predicted using gene ontology analysis. GBM cell migration and invasion were examined using wound healing and Transwell assays. Epithelial-mesenchymal transition (EMT) progression in GBM cell lines was detected with immunofluorescence and western blotting. The stemness activity of glioma stem-like cells (GSCs) was assessed by sphere formation assay and tumor xenograft model. miR-504 binding to the FZD7 (frizzled class receptor 7) 3' untranslated region (3'UTR) was validated using dual luciferase reporter assay. TOP/FOP Flash assays were conducted to determine the effects of miR-504 on Wnt/ß-catenin signaling. RESULTS: Analysis of TCGA transcriptomic data showed that low miR-504 expression correlated with ME subtype transition and poor survival in patients with GBM. Functional experiments showed that miR-504 overexpression suppressed malignant behaviors of GBM cells, such as migration, invasion, EMT, and stemness activity. Furthermore, miR-504 was a negative regulator of the Wnt-ß-catenin pathway by directly repressing FZD7 expression, and FZD7 overexpression reversed the EMT inhibition caused by miR-504. Moreover, the low miR-504/FZD7 expression ratio was a ME subtype marker and could serve as a significant prognostic indicator and predict the clinical outcome of chemotherapy and radiotherapy for patients with GBM in TCGA dataset. CONCLUSIONS: Our results suggest that miR-504 suppresses the aggressive biological processes associated with the ME phenotype of GBM and could be a potential candidate for therapeutic applications in these malignant brain tumors.

Astrocytoma progression scoring system based on the WHO 2016 criteria.

Diffuse astrocytoma (including glioblastoma) is morbid with a worse prognosis than other types of glioma. Therefore, we sought to build a progression-associated score to improve malignancy and prognostic predictions for astrocytoma. The astrocytoma progression (AP) score was constructed through bioinformatics analyses of the training cohort (TCGA RNA-seq) and included 18 genes representing distinct aspects of regulation during astrocytoma progression. This classifier could successfully discriminate patients with distinct prognoses in the training and validation (REMBRANDT, GSE16011 and TCGA-GBM Microarray) cohorts (P < 0.05 in all cohorts) and in different clinicopathological subgroups. Distinct patterns of somatic mutations and copy number variation were also observed. The bioinformatics analyses suggested that genes associated with a higher AP score were significantly involved in cancer progression-related biological processes, such as the cell cycle and immune/inflammatory responses, whereas genes associated with a lower AP score were associated with relatively normal nervous system biological processes. The analyses indicated that the AP score was a robust predictor of patient survival, and its ability to predict astrocytoma malignancy was well elucidated. Therefore, this bioinformatics-based scoring system suggested that astrocytoma progression could distinguish patients with different underlying biological processes and clinical outcomes, facilitate more precise tumour grading and possibly shed light on future classification strategies and therapeutics for astrocytoma patients.

ON-Type Retinal Ganglion Cells are Preferentially Affected in STZ-Induced Diabetic Mice.

Purpose: We investigate morphologic and physiologic alterations of ganglion cells (GCs) in a streptozocin (STZ)-induced diabetic mouse model. Methods: Experiments were conducted in flat-mount retinas of mice 3 months after the induction of diabetes. Changes in morphology of four subtypes of GCs (ON-type RGA2 [ON-RGA2], OFF-type RGA2 [OFF-RGA2], ON-type RGC1 [ON-RGC1], and ON-OFF type RGD2 [ON-OFF RGD2]) were characterized in Thy1-YFP transgenic mice. Using whole-cell patch-clamp recording, passive membrane properties and action potential (AP) firing properties were further investigated in transient ON- and OFF-RGA2 cells. Results: Morphologic parameters were significantly altered in the dendrites branching in the ON sublamina of the inner plexiform layer (IPL) for ON-RGA2 cells and ON-OFF RGD2 cells. Much less significant changes, if any, were seen in those arborizing in the OFF sublamina of the IPL for OFF-RGA2 and ON-OFF RGD2 cells. No detectable changes in morphology were seen in RGC1 cells. Electrophysiologically, increased resting membrane potentials and decreased membrane capacitance were found in transient ON-RGA2 cells, but not in transient OFF-RGA2 cells. Similar alterations in AP firing properties, such as an increase in AP width and reduction in maximum spiking rate, were shared by these two subtypes. Furthermore, in response to depolarizing current injections, both cells generated more APs suggesting an enhanced excitability of these cells in diabetic conditions. Conclusions: These differential changes in morphology and electrophysiology in subtypes of GCs may be responsible for reduced contrast sensitivity known to occur during the early stage of diabetic retinopathy.

Human Thalamic-Prefrontal Peduncle Connectivity Revealed by Diffusion Spectrum Imaging Fiber Tracking.

The thalamic-prefrontal peduncle (TPP) is a large bundle connecting the thalamus and prefrontal cortex. The definitive structure and function of the TPP are still controversial. To investigate the connectivity and segmentation patterns of the TPP, we employed diffusion spectrum imaging with generalized q-sampling reconstruction to perform both subject-specific and template-based analyses. Our results confirmed the trajectory and spatial relationship of the TPP in the human brain and identified the connection areas in the prefrontal cortex. The TPP-connecting areas identified based on Brodmann areas (BAs) were BAs 8-11 and 45-47. Based on the automated anatomical atlas, these areas were the medial superior frontal gyrus, superior frontal gyrus, middle frontal gyrus, pars triangularis, pars orbitalis, anterior orbital gyrus, and lateral orbital gyrus. In addition, we identified the TPP connection areas in the thalamus, including the anterior and medial nuclei, and the lateral dorsal/lateral posterior nuclei. TPP fibers connected the thalamus with the ipsilateral prefrontal BAs 11, 47, 10, 46, 45, 9, and 8 seriatim from medial to lateral, layer by layer. Our results provide further details of the thalamic-prefrontal peduncle structure, and may aid future studies and a better understanding of the functional roles of the TPP in the human brain.

A tumor-suppressive microRNA, miR-504, inhibits cell proliferation and promotes apoptosis by targeting FOXP1 in human glioma.

MicroRNAs (miRNAs) have been proposed as useful prognostic cancer biomarkers and as potential molecular targets for treating various cancers. Previous findings have indicated that miR-504 is dysregulated and involved in tumorigenesis of several types of cancer. However, the biological role of miR-504 in glioma remains unclear. In this study, we showed that miR-504 expression was markedly decreased in both glioma tissues and cell lines and that miR-504 downregulation significantly correlated with aggressive clinicopathological features and poor prognosis for glioma patients. In addition, miR-504 overexpression inhibited cell proliferation, induced cell cycle arrest, and promoted apoptosis in glioma cell lines. Furthermore, we identified forkhead box protein P1 (FOXP1) as a direct target of miR-504 using microarray analysis and a luciferase assay. Moreover, we demonstrated that miR-504 regulated glioma tumorigenesis by downregulating FOXP1 expression. Our results suggest that miR-504 might function as an important suppressor of glioma tumorigenesis and could serve as a promising candidate for therapeutic applications in glioma treatment.

Up-regulation of microRNA-15b correlates with unfavorable prognosis and malignant progression of human glioma.

Recent studies have demonstrated that microRNA-15b (miR-15b) regulates cell cycle progression, proliferationnd apoptosis in glioma cells by targeting Cyclins. However, the clinical significance of miR-15b in human glioma remains unclear. Therefore, the aim of this study was to investigate the significance of miR-15b expression in diagnosis, prognosis and malignant progression of glioma. Quantitative real-time reverse transcriptive-PCR (qRT-PCR) was performed to examine miR-15b expression levels in 76 glioma tissues (13 grade II, 13 grade III and 50 grade IV gliomas) and seven glioma cell lines, as well as 10 non-neoplastic brain tissues and human astrocyte as control. MiR-15b showed significant increased expression in high-grade gliomas (P≤0.001) and glioma cells (fold change 2.8-7.6) relative to non-neoplastic brains and astrocyte, respectively. Additionally, high miR-15b expression was significantly associated with advanced WHO grade (P≤0.001), advanced patient age (P≤0.001) and low Karnofsky performance score (KPS, P≤0.001). Furthermore, Kaplan-Meier survival analysis and Cox regression analysis showed that patients with high miR-15b expression had significantly poor overall survival rate (P≤0.001) and miR-15b expression was an independent prognosis-predicting factor for glioma patients (P≤0.001; risk ratio=5.6), respectively. Moreover, miR-15b expression was examined in seven independent patients with primary grade II or III gliomas that spontaneously progressed to grade III or IV gliomas. Statistically significant higher expression (P=0.01) in the recurrent tumor compared with the corresponding primary tumor was observed in all of the seven patients. Our results suggest that miR-15b may be a prognostic predictor and be involved in malignant progression of glioma.

High miR-196a and low miR-367 cooperatively correlate with unfavorable prognosis of high-grade glioma.

Identification of microRNAs (miRNAs) could be beneficial for the diagnosis and prognosis of glioma. Therefore, we attempted to identify and develop specific miRNAs as prognostic and predictive markers for glioma patients. We compared the expression profiles of 365 miRNAs between 4 glioblastomas (GBMs, WHO grade IV) and 4 anaplastic astrocytomas (AAs, WHO grade III) using miRNA qPCR Array. MiR-196a (P = 0.004, fold change = 289.86) and miR-367 (P = 0.044, fold change = 0.03) were identified as the most up-regulated and down-regulated miRNAs in GBMs compared with AAs, respectively. We subsequently examined miR-196a and miR-367 expression levels in an independent series of 63 gliomas including 50 GBMs and 13 AAs, as well as 10 non-neoplastic brain tissues, and statistically analyzed the associations between miRNA expression and clinicopathological characteristics and survivals of these glioma patients. MiR-196a and miR-367 showed significant increased and decreased expression in high-grade gliomas relative to non-neoplastic brains, as well as in GBMs versus AAs, respectively. Additionally, high-miR-196a and low-miR-367 expression, alone or in combination, statistically correlated with aggressive clinicopathological features of gliomas. Furthermore, overall survivals of glioma patients with high-miR-196a, low-miR-367 and high-miR-196a/low-miR-367 expression tended to be shorter than the corresponding control groups (all P ≤ 0.001). Moreover, multivariate analysis indicated high-miR-196a/low-miR-367 as an independent prognostic indicator for glioma patients (P = 0.005, risk ratio = 1.8). Our results suggested that both high-miR-196a and low-miR-367 expression may be associated with aggressive progression and unfavorable clinical outcome in glioma patients. And combination of high-miR-196a and low-miR-367 expression may be a novel biomarker in identifying a poor prognosis group of high-grade glioma.

Identification of low miR-105 expression as a novel poor prognostic predictor for human glioma.

Glioma is the most common and aggressive brain tumor with poor clinical outcome. Identification and development of new biomarkers could be beneficial for diagnosis and prognosis of glioma patients. Recent studies have showed evidences that dysregulation of microRNAs (miRNAs) is involved in glioma tumorigenesis. Therefore, we attempted to identify specific miRNAs as prognostic and predictive markers for glioma. We statistically compared expression profile of 365 miRNAs between WHO grade IV and grade III gliomas, by qRT-PCR. MiR-105 was identified as a remarkably decreased miRNA in grade IV gliomas compared with grade III gliomas (P=0.012, fold change =0.04). We subsequently examined its expression levels in an independent series of gliomas, and statistically analyzed the associations between miR-105 expression and clinicopathological characteristics and survivals of these glioma patients. MiR-105 showed remarkably decreased expression in gliomas as compared to non-neoplastic brains. And grade IV gliomas had significantly lower miR-105 expression compared with grade III and II gliomas (both P<0.001). Additionally, low miR-105 expression was statistically associated with advanced tumor grade, advanced patient's age and low pre-operative Karnofsky performance score (all P<0.001). Furthermore, patients with low miR-105 expression had significantly poorer survival by Kaplan-Meier method (P<0.001). Multivariate analysis indicated miR-105 as an independent prognostic indicator for glioma patients (P=0.018, risk ratio =4.2). Our results suggested that low expression of miR-105 may correlate with unfavorable clinical outcome and be involved in tumorigenesis and aggressive progression of glioma. And miR-105 may be a novel biomarker in prognostic prediction for glioma.

Downregulation of microRNA-504 is associated with poor prognosis in high-grade glioma.

Several previous reports indicated that microRNA-504 (miR-504) has an oncogenic function through negatively regulating p53. On the other hand, a recent study revealed that miR-504 inhibits cancer cell proliferation through targeting CDK6 in hypopharyngeal squamous cell carcinoma (HSCC), suggesting the tumor suppressive role of this miRNA. However, the role of miR-504 in human malignant glioma remains unclear. Therefore, the aim of this study was to investigate the clinical significance of miR-504 expression in high pathological grade glioma. Quantitative real-time reverse transcriptive-PCR (qRT-PCR) was performed to examine miR-504 expression levels in 63 glioma tissues including 13 anaplastic astrocytomas (AA, WHO grade III) and 50 glioblastomas (GBM, WHO grade IV), as well as 10 non-neoplastic brain tissues. Associations between miR-504 expression and clinicopathological factors and prognosis of glioma patients were statistically analyzed. MiR-504 showed significant decreased expression levels both in AAs and GBMs relative to non-neoplastic brains (P ≤ 0.001, respectively). Additionally, low expression level of miR-504 was significantly associated with advanced WHO grade (P = 0.01). Moreover, Kaplan-Meier survival analysis showed that patients with low expression of miR-504 had significantly poor survival rate (P = 0.002). Cox regression analysis showed that miR-504 expression was independent prognosis-predicting factor for malignant glioma patients (P = 0.038; risk ration = 2.5). Our results suggest that miR-504 may be a prognostic predictor and be involved in tumorigencity as a tumor suppressor of malignant glioma.