Macrophage Migration Inhibitory Factor as a Potential Plasma Biomarker of Cognitive Impairment in Cerebral Small Vessel Disease.

As the pathogenesis of cerebral small vessel disease with cognitive impairment (CSVD-CI) remains unclear, identifying effective biomarkers can contribute to the clinical management of CSVD-CI. This study recruited 54 healthy controls (HCs), 60 CSVD-CI patients, and 57 CSVD cognitively normal (CSVD-CN) patients. All participants underwent neuropsychological assessments and multimodal magnetic resonance imaging. Macrophage migration inhibitory factors (MIFs) were assessed in plasma. The least absolute shrinkage and selection operator model was used to determine a composite marker. Compared with HCs or CSVD-CN patients, CSVD-CI patients had significantly increased plasma MIF levels. In CSVD-CI patients, plasma MIF levels were significantly correlated with multiple cognitive assessment scores, plasma levels of blood-brain barrier (BBB)-related indices, white matter hyperintensity Fazekas scores, and the mean amplitude of low-frequency fluctuation in the right superior temporal gyrus. Higher plasma MIF levels were significantly associated with worse global cognition and information processing speed in CSVD-CI patients. The composite marker (including plasma MIF) distinguished CSVD-CI patients from CSVD-CN and HCs with >80% accuracy. Meta-analysis indicated that blood MIF levels were significantly increased in CSVD-CI patients. In conclusion, plasma MIF is a potential biomarker for early identification of CSVD-CI. Plasma MIF may play a role in cognitive decline in CSVD through BBB dysfunction and changes in white matter hyperintensity and brain activity.

Potential Association of Neutrophil Extracellular Traps With Cognitive Impairment in Cerebral Small Vessel Disease.

No acceptable biomarker can facilitate the early identification of cognitive impairment associated with cerebral small vessel disease (CSVD) in the older persons. The neutrophil extracellular traps (NETs) in the inflammation response of circulatory and central systems are essential in destroying the blood-brain barrier. The present study aims to explore the potential associations of plasma NETs with cognitive performance in CSVD. We recruited 146 CSVD patients and 66 healthy controls (HCs), and comprehensive neuropsychological assessments and multimodal magnetic resonance imaging were conducted. Three NETs markers, namely citrullination of histone H3, neutrophil elastase-DNA, and myeloperoxidase (MPO)-DNA, and 4 oxidative stress-related indexes in plasma samples, were measured. The plasma levels of 3 NETs markers were more significantly elevated in CSVD patients than in HCs. Significant correlations of the 3 NETs markers were observed with multiple cognitive domain scores. Furthermore, higher plasma malondialdehyde and NETs levels were significantly associated with the worse Montreal Cognitive Assessment scores among CSVD patients. Moreover, plasma MPO-DNA levels significantly mediated the effect of the amplitude of low-frequency fluctuation value within the bilateral caudate and the scores of global cognitive function, executive function, and information processing speed. Additionally, a panel of 3 NETs markers had the highest area under the curve value to distinguish the cognitively impaired CSVD patients from HCs and nonimpaired ones. Therefore, plasma NETs may be potential biomarkers for early diagnosis of CSVD-related cognitive impairment. Activated lipid peroxidation in circulation and impaired caudate function support potential associations of plasma NETs in cognitively impaired CSVD patients.

Alteration and clinical potential in gut microbiota in patients with cerebral small vessel disease.

Background: Cerebral small vessel disease (CSVD) is a cluster of microvascular disorders with unclear pathological mechanisms. The microbiota-gut-brain axis is an essential regulatory mechanism between gut microbes and their host. Therefore, the compositional and functional gut microbiota alterations lead to cerebrovascular disease pathogenesis. The current study aims to determine the alteration and clinical value of the gut microbiota in CSVD patients. Methods: Sixty-four CSVD patients and 18 matched healthy controls (HCs) were included in our study. All the participants underwent neuropsychological tests, and the multi-modal magnetic resonance imaging depicted the changes in brain structure and function. Plasma samples were collected, and the fecal samples were analyzed with 16S rRNA gene sequencing. Results: Based on the alpha diversity analysis, the CSVD group had significantly decreased Shannon and enhanced Simpson compared to the HC group. At the genus level, there was a significant increase in the relative abundances of Parasutterella, Anaeroglobus, Megasphaera, Akkermansia, Collinsella, and Veillonella in the CSVD group. Moreover, these genera with significant differences in CSVD patients revealed significant correlations with cognitive assessments, plasma levels of the blood-brain barrier-/inflammation-related indexes, and structural/functional magnetic resonance imaging changes. Functional prediction demonstrated that lipoic acid metabolism was significantly higher in CSVD patients than HCs. Additionally, a composite biomarker depending on six gut microbiota at the genus level displayed an area under the curve of 0.834 to distinguish CSVD patients from HCs using the least absolute shrinkage and selection operator (LASSO) algorithm. Conclusion: The evident changes in gut microbiota composition in CSVD patients were correlated with clinical features and pathological changes of CSVD. Combining these gut microbiota using the LASSO algorithm helped identify CSVD accurately.

National Brain Tumour Registry of China (NBTRC) statistical report of primary brain tumours diagnosed in China in years 2019-2020.

Background: The lack of a well-designed brain tumour registry with standardized pathological diagnoses in underdeveloped countries hinders the ability to compare epidemiologic data across the globe. The National Brain Tumour Registry of China (NBTRC), created in January 2018, is the first multi-hospital-based brain tumour registry in China. Patient data reported to the NBTRC in years 2019-2020 were assessed. Methods: Tumour pathology was based on the 2016 World Health Organization (WHO) classification of tumours of the central nervous system and ICD-O-3. The anatomical site was coded per the Surveillance, Epidemiology, and End Results (SEER) solid tumour module (version of July 2019). The cases were tabulated by histology and anatomical site. Categorical variables were reported as numbers (percentages). The distribution of tumours by age (0-14, 15-19, 20-39, 40-64, and 65+ years) was analysed. Findings: There were a total of 25,537 brain tumours, foremost among them meningioma (23.63%), followed by tumours of the pituitary (23.42%), and nerve sheath tumours (9.09%). Glioblastoma, the most common and lethal form of primary brain cancer in adults, represented 8.56% of all cases. Of note, 6.48% of the malignant tumours were located in the brain stem. The percentage of malignant brain tumours decreased with increasing age, 24.08% in adults (40+ years), 30.25% in young adults (20-39 years), 35.27% in adolescents (15-19 years), and 49.83% in children (0-14 years). Among the 2107 paediatric patients, the most common sites were ventricle (17.19%), brainstem (14.03%), pituitary and craniopharyngeal duct (13.4%), and cerebellum (12.3%), a distribution that differed from that of the entire cohort. The histology distribution was also unique in children, with glioblastoma much less incident compared to the whole cohort (3% vs. 8.47%, p < 0.01). 58.80% of all patients chose higher-level neurosurgical hospitals outside of their province of residence. The median in-hospital length of stay (LOS) for the various pathologies ranged from 11 to 19 days. Interpretation: The histological and anatomical site distribution of brain tumours in the NBTRC was statistically different in the subgroup of children (0-14 years). Patient choice of pursuing trans-provincial treatment was common and the in-hospital LOS was longer compared to that reported in similar European and American patient populations, which merits further attention. Funding: The National Key Research and Development Program of China (2015BAI12B04, 2013BAI09B03, 2014BAI04B01, and 2021YFF1201104) and Chinese National Natural Science Foundation of China (81971668).

Combination of platelet-to-lymphocyte ratio and D-dimer for the identification of cardiogenic cerebral embolism in non-valvular atrial fibrillation.

Background: Non-valvular atrial fibrillation (NVAF) is the most common cause of cardiogenic cerebral embolism (CCE). However, the underlying mechanism between cerebral embolism and NVAF is indefinite, and there is no effective and convenient biomarker to identify potential risk of CCE in patients with NVAF in clinic. The present study aims to identify risk factors for interpreting the potential association of CCE with NVAF and providing valuable biomarkers to predict the risk of CCE for NVAF patients. Methods: 641 NVAF patients diagnosed with CCE and 284 NVAF patients without any history of stroke were recruited in the present study. Clinical data including demographic characteristics, medical history, and clinical assessments, were recorded. Meanwhile, Blood cell counts, lipid profiles, high-sensitivity C-reactive protein, and coagulation function-related indicators were measured. Least absolute shrinkage and selection operator (LASSO) regression analysis was utilized to build a composite indicator model based on the blood risk factors. Results: (1) CCE patients had significantly increased neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), and D-dimer levels as compared with patients in the NVAF group, and these three indicators can distinguish CCE patients from ones in the NVAF group with an area under the curve (AUC) value of over 0.750, respectively. (2) Using the LASSO model, a composite indicator, i.e., the risk score, was determined based on PLR and D-dimer and displayed differential power for distinguishing CCE patients from NVAF patients with an AUC value of over 0.934. (3) The risk score was positively correlated with the National Institutes of Health Stroke Scale and CHADS2 scores in CCE patients. (4) There was a significant association between the change value of the risk score and the recurrence time of stroke in initial CCE patients. Conclusions: The PLR and D-dimer represent an aggravated process of inflammation and thrombosis in the occurrence of CCE after NVAF. The combination of these two risk factors can contribute to identifying the risk of CCE for patients with NVAF with an accuracy of 93.4%, and the greater in change of composite indicator, the shorter in the recurrence of CCE for NVAF patients.

Marrow Mesenchymal Stem Cell-Derived Exosomes Upregulate Astrocytic Glutamate Transporter-1 Expression via miR-124/mTOR Pathway against Oxygen-Glucose Deprivation/Reperfusion Injury.

BACKGROUND: Experimental investigations have reported the efficacy of marrow mesenchymal stem cell-derived exosomes (MSC-Exos) for the treatment of ischemic stroke. The therapeutic mechanism, however, is still unknown. The purpose of the study is to show whether MSC-Exos increases astrocytic glutamate transporter-1 (GLT-1) expression in response to ischemic stroke and to investigate further mechanisms. METHODS AND RESULTS: An in vitro ischemia model (oxygen-glucose deprivation/reperfusion, OGD/R) was used. MSC-Exos was identified by Western blot (WB) and transmission electron microscopy (TEM). To further investigate the mechanism, MSC-Exos, miR-124 inhibitor, and mimics, and a mTOR pathway inhibitor (rapamycin, Rap) were used. The interaction between GLT-1 and miR-124 was analyzed by luciferase reporter assay. The GLT-1 RNA expression and miR-124 was assessed by quantitative real-time polymerase chain reaction (qRTPCR). The protein expressions of GLT-1, S6, and pS6 were detected by WB. Results demonstrated that MSC-Exos successfully inhibited the decrease of GLT-1 and miR-124 expression and the increase of pS6 expression in astrocytes after OGD/R. miR-124 inhibitor suppressed the effect of MSC-Exos on GLT-1 upregulation after OGD/R. Rapamycin notably decreased pS6 expression with significantly higher GLT-1 expression in astrocytes injured by OGD/R. Luciferase activity of the reporter harboring the wild-type or mutant GLT-1 3'UTR was not inhibited by miR-124 mimics. Further results showed that the inhibiting effect of MSC-Exos on pS6 expression and promoting effect of MSC-Exos on GLT-1 expression could be reversed by miR-124 inhibitor after OGD/R; meanwhile, the above conditions could be reversed again by rapamycin. CONCLUSIONS: Results show that miR-124 and the mTOR pathway are involved in regulation of MSC-Exos on GLT-1 expression in astrocytes injured by OGD/R. miR-124 does not directly target GLT-1. MSC-Exos upregulates GLT-1 expression via the miR-124/mTOR pathway in astrocytes injured by OGD/R.

Potential of brain age in identifying early cognitive impairment in subcortical small-vessel disease patients.

Background: Reliable and individualized biomarkers are crucial for identifying early cognitive impairment in subcortical small-vessel disease (SSVD) patients. Personalized brain age prediction can effectively reflect cognitive impairment. Thus, the present study aimed to investigate the association of brain age with cognitive function in SSVD patients and assess the potential value of brain age in clinical assessment of SSVD. Materials and methods: A prediction model for brain age using the relevance vector regression algorithm was developed using 35 healthy controls. Subsequently, the prediction model was tested using 51 SSVD patients [24 subjective cognitive impairment (SCI) patients and 27 mild cognitive impairment (MCI) patients] to identify brain age-related imaging features. A support vector machine (SVM)-based classification model was constructed to differentiate MCI from SCI patients. The neurobiological basis of brain age-related imaging features was also investigated based on cognitive assessments and oxidative stress biomarkers. Results: The gray matter volume (GMV) imaging features accurately predicted brain age in individual patients with SSVD (R 2 = 0.535, p < 0.001). The GMV features were primarily distributed across the subcortical system (e.g., thalamus) and dorsal attention network. SSVD patients with age acceleration showed significantly poorer Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA) scores. The classification model based on GMV features could accurately distinguish MCI patients from SCI patients (area under the curve = 0.883). The classification outputs of the classification model exhibited significant associations with MoCA scores, Trail Making Tests A and B scores, Stroop Color and Word Test C scores, information processing speed total scores, and plasma levels of total antioxidant capacity in SSVD patients. Conclusion: Brain age can be accurately quantified using GMV imaging data and shows potential clinical value for identifying early cognitive impairment in SSVD patients.

SHF Acts as a Novel Tumor Suppressor in Glioblastoma Multiforme by Disrupting STAT3 Dimerization.

Sustained activation of signal transducer and activator of transcription 3 (STAT3) is a critical contributor in tumorigenesis and chemoresistance, thus making it an attractive cancer therapeutic target. Here, SH2 domain-containing adapter protein F (SHF) is identified as a tumor suppressor in glioblastoma Multiforme (GBM) and its negative regulation of STAT3 activity is characterized. Mechanically, SHF selectively binds and inhibits acetylated STAT3 dimerization without affecting STAT3 phosphorylation or acetylation. Additionally, by blocking STAT3-DNMT1 (DNA Methyltransferase 1) interaction, SHF relieves methylation of tumor suppressor genes. The SH2 domain is documented to be essential for SHF's actions on STAT3, and almost entirely replaces the functions of SHF on STAT3 independently. Moreover, the peptide C16 a peptide derived from the STAT3-binding sites of SHF inhibits STAT3 dimerization and STAT3/DNMT1 interaction, and achieves remarkable growth inhibition in GBM cells in vitro and in vivo. These findings strongly identify targeting of the SHF/STAT3 interaction as a promising strategy for developing an optimal STAT3 inhibitor and provide early evidence of the potential clinical efficacy of STAT3 inhibitors such as C16 in GBM.

Clinical Observation and Value Analysis of Endovascular Interventional Therapy for Intracranial Venous Sinus Thrombosis.

The main aim of this study was to investigate the therapeutic effect of endovascular interventional therapy on cerebral venous sinus thrombosis (CVST). 137 patients with CVST were included, 92 patients were treated with interventional therapy, and 45 patients were treated with conventional anticoagulant therapy. Through endovascular therapy (EVT) combined with therapy, the patients were treated with EVT in combination with conventional anticoagulant therapy, and the prognosis of the two groups of patients was evaluated. The results showed that 26 patients were complicated with female-specific infections in the combined EVT group, and 7 patients had female-specific infections in the simple anticoagulant therapy (LMWH) group. In terms of central nervous system infections, the EVT group was significantly lower than the LMWH group, P < 0.001, and the difference was statistically significant. There were 2 cases of EVT involving the inferior sagittal sinus and 12 cases of LMWH involving the inferior sagittal sinus, P < 0.001, and the difference had statistical significance. Through the RANKIN scale (mRS) score, it was classified as complete recovery and good prognosis (dependent variable). The patients receiving EVT with good prognosis (96.7%) were more than those receiving simple anticoagulant therapy (84.4%), and 78.3% were completely recovered after EVT, and 77.5% were completely recovered after anticoagulant therapy. Therefore, it can be concluded that gender, malignant tumors, thrombosis, and sinuses are all risk factors affecting the prognosis of patients; both endovascular interventional therapy and anticoagulant therapy can significantly improve the prognosis of patients.

HOXC6 impacts epithelial-mesenchymal transition and the immune microenvironment through gene transcription in gliomas.

BACKGROUND: Gliomas are the most common primary malignant tumours of the central nervous system (CNS). To improve the prognosis of glioma, it is necessary to identify molecular markers that may be useful for glioma therapy. HOXC6, an important transcription factor, is involved in multiple cancers. However, the role of HOXC6 in gliomas is not clear. METHODS: Bioinformatic and IHC analyses of collected samples (n = 299) were performed to detect HOXC6 expression and the correlation between HOXC6 expression and clinicopathological features of gliomas. We collected clinical information from 177 to 299 patient samples and estimated the prognostic value of HOXC6. Moreover, cell proliferation assays were performed. We performed Gene Ontology (GO) analysis and gene set enrichment analysis (GSEA) based on ChIP-seq and public datasets to explore the biological characteristics of HOXC6 in gliomas. RNA-seq was conducted to verify the relationship between HOXC6 expression levels and epithelial-mesenchymal transition (EMT) biomarkers. Furthermore, the tumour purity, stromal and immune scores were evaluated. The relationship between HOXC6 expression and infiltrating immune cell populations and immune checkpoint proteins was also researched. RESULTS: HOXC6 was overexpressed and related to the clinicopathological features of gliomas. In addition, knockdown of HOXC6 inhibited the proliferation of glioma cells. Furthermore, increased HOXC6 expression was associated with clinical progression. The biological role of HOXC6 in gliomas was primarily associated with EMT and the immune microenvironment in gliomas. High HOXC6 expression was related to high infiltration by immune cells, a low tumour purity score, a high stromal score, a high immune score and the expression of a variety of immune checkpoint genes, including PD-L1, B7-H3 and CLTA-4. CONCLUSIONS: These results indicated that HOXC6 might be a key factor in promoting tumorigenesis and glioma progression by regulating the EMT signalling pathway and might represent a novel immune therapeutic target in gliomas.

MicroRNA-mediated regulation of reactive astrocytes in central nervous system diseases.

Astrocytes (AST) are abundant glial cells in the human brain, accounting for approximately 20-50% percent of mammalian central nervous system (CNS) cells. They display essential functions necessary to sustain the physiological processes of the CNS, including maintaining neuronal structure, forming the blood-brain barrier, coordinating neuronal metabolism, maintaining the extracellular environment, regulating cerebral blood flow, stabilizing intercellular communication, participating in neurotransmitter synthesis, and defending against oxidative stress et al. During the pathological development of brain tumors, stroke, spinal cord injury (SCI), neurodegenerative diseases, and other neurological disorders, astrocytes undergo a series of highly heterogeneous changes, which are called reactive astrocytes, and mediate the corresponding pathophysiological process. However, the pathophysiological mechanisms of reactive astrocytes and their therapeutic relevance remain unclear. The microRNAs (miRNAs) are essential for cell differentiation, proliferation, and survival, which play a crucial role in the pathophysiological development of CNS diseases. In this review, we summarize the regulatory mechanism of miRNAs on reactive astrocytes in CNS diseases, which might provide a theoretical basis for the diagnosis and treatment of CNS diseases.

Effect of astaxanthin on neuron damage, inflammatory factors expressions and oxidative stress in mice with subarachnoid hemorrhage.

OBJECTIVE: This study aimed to explore the effect of astaxanthin (ATX) on neuron damage, inflammatory factor expression and oxidative stress in mice with subarachnoid hemorrhage (SAH). METHODS: Specific-pathogen-free, 'Institute of Cancer Research', male mice were randomly divided into four groups: SAH group, sham group, SAH + placebo group (SAH + Vehicle group) and SAH + ATX group. Neurological function was scored in each group. Brain water content, reactive oxygen species (ROS) content and inflammatory factor levels in the brain were detected by wet-dry weighting method, DCFH-DA fluorescent probe staining method and ELISA, respectively. Expression of NADPH oxidase 2 (NOX2), glial fibrillary acidic protein (GFAP) and apoptosis-related proteins Bax and Bcl-2 were detected by Western blot and quantitative real-time polymerase chain reaction. Neuronal apoptosis was detected by TUNEL staining. RESULTS: Compared with sham group, neurological score, brain water content and ROS content in the other three groups increased significantly (all P<0.05). Neurological score, brain water content and ROS content in SAH + ATX group were lower than those in SAH group (all P<0.05). Compared with the sham group, there was increased expression of interleukin (IL)-6, IL-17 and tumor necrosis factor α (TNF-α), and increased neuronal apoptosis, as well as enhanced expression of NOX2, GFAP and Bax; while there was decreased IL-10 expression, and declined Bcl-2 expression, in the other three groups (all P<0.05). There was decreased expression of IL-6, IL-17 and TNF-α, declined expressions of NOX2, GFAP and Bax, and lowered neuronal apoptosis; while there was increased IL-10 expression, and enhanced Bcl-2 expression, in SAH + ATX group as compared to SAH group (all P<0.05). All indicators between SAH group and SAH + Vehicle group showed no significant differences (all P>0.05). CONCLUSION: Astaxanthin can decrease neuron damage, inhibit inflammatory response, and improve oxidative stress in SAH mice. Thus, astaxanthin is a method for treating SAH.

Noncoding RNAs involved in the STAT3 pathway in glioma.

Glioma is the most common malignant primary brain tumour in adults. Despite improvements in neurosurgery and radiotherapy, the prognosis of glioma patients remains poor. One of the main limitations is that there are no proper clinical therapeutic targets for glioma. Therefore, it is crucial to find one or more effective targets. Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family of genes. Abnormal expression of STAT3 is involved in the process of cell proliferation, migration, invasion, immunosuppression, angiogenesis, dryness maintenance, and resistance to radiotherapy and chemotherapy in glioma. Therefore, STAT3 has been considered an ideal therapeutic target in glioma. Noncoding RNAs (ncRNAs) are a group of genes with limited or no protein-coding capacity that can regulate gene expression at the epigenetic, transcriptional and posttranscriptional level. In this review, we summarized the ncRNAs that are correlated with the ectopic expression of STAT3 in glioma.

Bioinformatics Analysis of Expression Profiles and Prognostic Values of the Signal Transducer and Activator of Transcription Family Genes in Glioma.

Signal transducer and activator of transcription (STAT) family genes-of which there are seven members: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6-have been associated with the progression of multiple cancers. However, their prognostic values in glioma remain unclear. In this study, we systematically investigated the expression, the prognostic value, and the potential mechanism of the STAT family genes in glioma. The expression of STAT1/2/3/5A/6 members were significantly higher and positively correlated with IDH mutations, while the expression of STAT5B was lower and negatively correlated with IDH mutations in glioma. Survival analysis indicated that the upregulation of STAT1/2/3/5A/6 and downregulation of STAT5B expression was associated with poorer overall survival in glioma. Joint effects analysis of STAT1/2/3/5A/5B/6 expression suggested that the prognostic value of the group was more significant than that of each individual gene. Thus, we constructed a risk score model to predict the prognosis of glioma. The receiver operating characteristic curve and calibration curves showed good performance as prognostic indicators in both TCGA (The Cancer Genome Atlas) and the CGGA (Chinese Glioma Genome Atlas) databases. Furthermore, we analyzed the correlation between STAT expression with immune infiltration in glioma. The Protein-protein interaction network and enrichment analysis showed that STAT members and co-expressed genes mainly participated in signal transduction activity, Hepatitis B, the Jak-STAT signaling pathway, transcription factor activity, sequence-specific DNA binding, and the cytokine-mediated signaling pathway in glioma. In summary, our study analyzed the expression, prognostic values, and biological roles of the STAT gene family members in glioma, based on which we developed a new risk score model to predict the prognosis of glioma more precisely.

A positive feedback loop of LINC00662 and STAT3 promotes malignant phenotype of glioma.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been reported to be associated with tumorigenesis and development of glioma. LINC00662 has been involved in the pathogenesis of various human cancers. However, the mechanism underlying which LINC00662 exerts its role in glioma needs further exploration. In addition, regulation mechanism of LINC00662 expression in glioma remains unknown. METHODS AND MATERIALS: RT-qPCR was performed to evaluate the expression levels of LINC00662, miR-340-5p in glioma tissues and cell lines. The effect of LINC00662 and miR-340-5p in cell proliferation and invasion was assessed by Cell Counting Kit-8(CCK-8), clone colony formation and Transwell assay. Luciferase reporter assays and RNA immunoprecipitation assay validated the miR-340-5p-target relationships with LINC00662 or STAT3. CHIP-qPCR and Luciferase reporter assays were used to demonstrate the interaction between STAT3 and the promoter region of LINC00662. A tumor xenografts model was implemented to verify the effect of LINC00662 on glioma development in vivo. RESULTS: We found that LINC00662 was frequently highly expressed and related to the malignant phenotype of glioma. LINC00662 knockdown inhibited the proliferation, invasion and glioma genesis of glioma. LINC00662 acted as a ceRNA sponging miR-340-5p to protect the expression of STAT3. In addition, STAT3 was forced to the promoter region of LINC00662 and promoted its transcription. In vivo experiments demonstrated that targeting LINC00662 may be a potential strategy in glioma therapy. CONCLUSION: There was a positive regulation loop between LINC00662 and STAT3 in glioma. LINC00662 might be an oncogene in glioma. Targeting LINC00662 was a potential strategy in glioma therapy.

The expression and prognostic value of the epidermal growth factor receptor family in glioma.

BACKGROUND: The epidermal growth factor receptor (EGFR) family belongs to the transmembrane protein receptor of the tyrosine kinase I subfamily and has 4 members: EGFR/ERBB1, ERBB2, ERBB3, and ERBB4. The EGFR family is closely related to the occurrence and development of a variety of cancers. MATERIALS/METHODS: In this study, we used multiple online bioinformatics websites, including ONCOMINE, TCGA, CGGA, TIMER, cBioPortal, GeneMANIA and DAVID, to study the expression profiles, prognostic values and immune infiltration correlations of the EGFR family in glioma. RESULTS: We found that EGFR and ERBB2 mRNA expression levels were higher in glioblastoma (GBM, WHO IV) than in other grades (WHO grade II & III), while the ERBB3 and ERBB4 mRNA expression levels were the opposite. EGFR and ERBB2 were notably downregulated in IDH mutant gliomas, while ERBB3 and ERBB4 were upregulated, which was associated with a poor prognosis. In addition, correlation analysis between EGFR family expression levels and immune infiltrating levels in glioma showed that EGFR family expression and immune infiltrating levels were significantly correlated. The PPI network of the EGFR family in glioma and enrichment analysis showed that the EGFR family and its interactors mainly participated in the regulation of cell motility, involving integrin receptors and Rho family GTPases. CONCLUSIONS: In summary, the results of this study indicate that the EGFR family members may become potential therapeutic targets and new prognostic markers for glioma.

LINC01116 promotes the proliferation and invasion of glioma by regulating the microRNA­744­5p­MDM2­p53 axis.

Long non­coding RNAs (lncRNAs) have been implicated in the development and progression of tumors. However, the roles and underlying mechanisms of long intergenic non­protein coding RNA 1116 (LINC01116), a member of the lncRNA family, in glioma progression are largely unclear. The expression of LINC01116 and microRNA (miR)­744­5p in glioma tissues and cells was detected by reverse transcription­quantitative PCR. The influences of LINC01116 or miR­744­5p on cell proliferation and invasion were evaluated by Cell Counting Kit­8, colony formation and Transwell assays, and western blotting was used to detect the expression of p53 pathway proteins. A dual­luciferase reporter system was used to locate common binding sites between miR­744­5p and LINC01116 or the 3' untranslated region of E3 ubiquitin­protein ligase Mdm2 (MDM2). RNA immunoprecipitation was used to determine the interactions between RNAs and proteins. Moreover, a xenograft mouse model was constructed to investigate the effects of LINC01116 in vivo, followed by a TdT­mediated dUTP nick end labeling assay to determine the degree of apoptosis in nude mouse tumors. LINC01116 was found to be highly expressed in glioma tissues, which was associated with a malignant phenotype. LINC01116 promoted the proliferation and invasiveness of glioma cells, and inhibited the p53 pathway by preserving the expression of MDM2 mRNA via miR­744­5p sponging. Furthermore, a low degree of miR­744­5p expression was observed in glioma tissues, which was negatively associated with the expression of LINC01116. Overexpression of miR­744­5p inhibited the proliferation and invasiveness of glioma cells, which was rescued by LINC01116. Finally, LINC01116 knockdown inhibited tumor growth in nude mice. In conclusion, LINC01116 is aberrantly expressed and promotes the progression of glioma by regulating the miR­744­5p­MDM2­p53 pathway. In future, targeting LINC01116 may therefore be a potential therapeutic approach for patients with glioma.

MicroRNAs involved in the EGFR pathway in glioblastoma.

Glioblastoma (GBM) is the most common primary malignant tumor in adults, and its morbidity and mortality are very high. Although progress has been achieved in the treatment of GBM, such as surgery, chemotherapy and radiotherapy, in recent years, the prognosis of patients with GBM has not improved significantly. MicroRNAs (miRNAs) are endogenous noncoding single-stranded RNAs consisting of approximately 20-22 nucleotides that regulate gene expression at the posttranscriptional level by binding to target protein-encoding mRNAs. Notably, miRNAs regulate various carcinogenic pathways, one of which is the epidermal growth factor receptor (EGFR) signaling pathway, which controls cell proliferation, invasion, migration, angiogenesis and apoptosis. In this review, we summarize the novel discoveries of roles for miRNAs targeting the factors in the EGFR signaling pathway in the occurrence and development of GBM. In addition, we describe their potential roles as biomarkers for the diagnosis and prognosis of GBM and for determining the treatment resistance of GBM and the efficacy of therapeutic drugs.

LncRNA SNHG3, a potential oncogene in human cancers.

Long noncoding RNAs (lncRNAs) are composed of > 200 nucleotides; they lack the ability to encode proteins but play important roles in a variety of human tumors. A large number of studies have shown that dysregulated expression of lncRNAs is related to tumor oncogenesis and progression. Emerging evidence shows that SNHG3 is a novel oncogenic lncRNA that is abnormally expressed in various tumors, including osteosarcoma, liver cancer, lung cancer, etc. SNHG3 primarily competes as a competitive endogenous RNA (ceRNA) that targets tumor suppressor microRNAs (miRNAs) and ceRNA mechanisms that regulate biological processes of tumors. In addition, abnormal expression of SNHG3 is significantly correlated with patient clinical features. Upregulation of SNHG3 contributes to biological functions, including tumor cell proliferation, migration, invasion and EMT. Therefore, SNHG3 may represent a potential diagnostic and prognostic biomarker, as well as a novel therapeutic target.

The role of long noncoding RNA SNHG7 in human cancers (Review).

Long non-coding RNAs (lncRNAs) have been demonstrated to serve important roles in a variety of human tumor types. The lncRNA small nucleolar RNA host gene 7 (SNHG7) is associated with a variety of cancer types, such as esophageal cancer, breast cancer and gastric neoplasia. Based on previous studies that examined SNHG7 expression in tumors, it has become clear that SNHG7 modulates tumorigenesis and cancer progression by acting as a competing endogenous RNA. SNHG7 can sponge tumor-suppressive microRNAs and regulate downstream signaling pathways. In addition, overexpression of SNHG7 is associated with the clinical characteristics of patients with cancer by regulating cellular proliferation, invasion and metastasis and by inhibiting apoptosis via a variety of mechanisms of action. The function of SNHG7 in tumorigenesis and cancer progression indicates that it can potentially act as a novel therapeutic target or a diagnostic biomarker for cancer therapy or detection, respectively.