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BackgroundThe 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/methodsIn 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.ResultsWe 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.ConclusionsIn summary, the results of this study indicate that the EGFR family members may become potential therapeutic targets and new prognostic markers for 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.

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.

Long non-coding RNAs (lncRNAs) have been implicated in the development and progression of tumors. However, the roles and underlying mechanisms of long intergenic non-protein coding RNA 1116 (LINC01116), a member of the lncRNA family, in glioma progression are largely unclear. The expression of LINC01116 and microRNA (miR)-744-5p in glioma tissues and cells was detected by reverse transcription-quantitative PCR. The influences of LINC01116 or miR-744-5p on cell proliferation and invasion were evaluated by Cell Counting Kit-8, colony formation and Transwell assays, and western blotting was used to detect the expression of p53 pathway proteins. A dual-luciferase reporter system was used to locate common binding sites between miR-744-5p and LINC01116 or the 3′ untranslated region of E3 ubiquitin-protein 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 TdT-mediated 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 miR-744-5p sponging. Furthermore, a low degree of miR-744-5p expression was observed in glioma tissues, which was negatively associated with the expression of LINC01116. Overexpression of miR-744-5p 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 miR-744-5p-MDM2-p53 pathway. In future, targeting LINC01116 may therefore be a potential therapeutic approach for patients with glioma.

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.

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.

To date, the molecular mechanism underlying constitutive signal transducer and activator of transcription 3 (STAT3) activation in gliomas is largely unclear. In this study, we report that Smad6 is overexpressed in nuclei of glioma cells, which correlates with poor patient survival and regulates STAT3 activity via negatively regulating the Protein Inhibitors of Activated STAT3 (PIAS3). Mechanically, Smad6 interacts directly with PIAS3, and this interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and the Ring domain of PIAS3. Smad6 recruits Smurf1 to facilitate PIAS3 ubiquitination and degradation, which also depends on the MH2 domain and the PY motif of Smad6. Consequently, Smad6 reduces PIAS3-mediated STAT3 inhibition and promotes glioma cell growth and stem-like cell initiation. Moreover, the Smad6 MH2 transducible protein restores PIAS3 expression and subsequently reduces gliomagenesis. Collectively, we conclude that nuclear-Smad6 enhances glioma development by inducing PIAS3 degradation and subsequent STAT3 activity upregulation., In glioma STAT3 signaling contributes to gliomagenesis. Here, the authors show that Smad6 expression correlates with poor survival and is overexpressed in glioma cells, and regulates STAT3 activity via negatively regulating PIAS3.

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.

Background miR-129-5p has been reported to be abnormally expressed and plays an important role in the progression of various malignancies. However, its role in gliomas and its exact molecular mechanism need further research. Methods and materials RT-qPCR was performed to evaluate miR-129-5p and HOXC10 mRNA expression levels in tissues and cell lines. Cell proliferation was detected via Cell Counting Kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU) and clone formation assays. Luciferase assays were used to validate the binding of seeds between miR-129-5p and HOXC10. A tumor xenograft model was developed to study the effect of miR‐129-5p on glioma growth in vivo. Results miR-129-5p was expressed at low levels in glioma tissues and cell lines. miR-129-5p overexpression inhibited glioma proliferation, migration and invasion. miR-129-5p negatively and directly targeted HOXC10. At the same time, HOXC10 was upregulated in glioma cancer, and HOXC10 knockdown inhibited cell proliferation, migration and invasion. Conclusion miR-129-5p inhibits glioma development by altering HOXC10 expression and may therefore serve as a new diagnostic marker and therapeutic target for glioma in the future.

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.

Widespread invasiveness, represented by the invasion and migration, is the most important characteristic of glioblastoma multiforme (GBM) and is the main reason for therapeutic failure and recurrence of the tumor. Hypoxia is one of the main microenvironment in determining tumor invasiveness. Therefore, intense efforts aimed at improved therapeutics are ongoing to demonstrate the molecular mechanisms governing GBM migration and invasion. This study aims to explore the role of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and its relationship with hypoxia inducible factor-1α (HIF-1α) in the migration and invasion of human glioblastoma U87 cells under hypoxia. In the study, we found that hypoxia could activate the PI3K/Akt/mTOR pathway associated with the enhancements of the migration and invasion of human glioblastoma U87 cells. When the PI3K/Akt/mTOR pathway and HIF-1α were inhibited by the siRNAs or inhibitors, the migration and invasion of human glioblastoma U87 cells were suppressed. Meanwhile, the expression of HIF-1α could be inhibited by the siRNA or inhibitors of PI3K/Akt/mTOR pathway. The aforementioned results demonstrate that hypoxia could induce enhancements of migration and invasion by activating PI3K/Akt/mTOR pathway by targeting HIF-1α in human glioblastoma U87 cells, which provide a theoretical basis for the treatments of GBM by targeting the PI3K/Akt/mTOR/HIF-1α pathway.

Resveratrol (Res) has been reported to elicit many cellular responses including cell cycle arrest, differentiation, and apoptosis. This makes it a novel and potential anticancer agent. Moreover, the lipophilicity of Res raises the possibility of its application as a potential model drug in nanoparticle based delivery systems. Resveratrol is incorporated into mPEG-PCL based nanoparticles with high encapsulation efficiency due to its lipophilicity. The significant finding of the current study is that Res-loaded nanoparticles at lower concentration could lead to significantly higher cell death compared to equivalent dose of free Res and this difference of cytotoxicity could not be abrogated by the antioxidant Vitamin E. Furthermore, free Res shows significant less cytotoxicity than the equivalent dose of Res-loaded nanoparticles with the preconditioning of Vitamin E. Meanwhile, reactive oxygen species (ROS) determination revealed the significantly lower intracellular ROS levels in Res-treated cells compared to nanoparticle-treated cells. Therefore, the differential cytotoxicity between Res and Res-loaded nanoparticles may be mediated by the discrepancy of intracellular ROS levels. The present results suggest that Res-loaded nanoparticles could be a potential useful chemotherapeutic formulation for malignant glioma therapy and the development of traditional Chinese medicine with nanoscale drug formation warrants more intensive research in order to evaluate its clinical feasibility.

Temozolomide (TMZ), a DNA alkylating agent, represents the most important chemotherapeutic option for the treatment of glioblastoma in the clinic. Despite its frequent use, the therapeutic efficacy of TMZ remains very limited due to its frequent resistance in glioblastoma. Previous evidence suggested that curcumin (CUM), an ingredient of the Indian spice turmeric, is able to sensitize glioblastoma to TMZ treatment. However, the underlying molecular mechanism remains elusive. In the present study, we performed in vitro and in vivo experiments to evaluate the interaction of CUM and TMZ on the inhibition of glioblastoma and to investigate its potential mechanisms of action using U87MG cell lines and xenograft mouse models. We demonstrated that CUM enhanced the therapeutic response to TMZ in U87MG glioblastoma by enhancing apoptosis. We then proceeded to investigate the potential apoptotic signaling pathways that are involved. We observed a synergistic effect of the combination of CUM and TMZ in generating reactive oxygen species (ROS) production, suggesting that ROS may contribute to the impact of CUM on sensitizing TMZ treatment. We also showed that CUM and TMZ treatment alone significantly suppressed phosphorylated AKT and mTOR, whereas their combination achieved a more pronounced inhibitory effect. These data indicated that blockage of AKT/mTOR signaling appeared to contribute to the elevated apoptosis caused by the combination treatment with CUM and TMZ. In conclusion, this study provided molecular insights into the effects of CUM on the therapeutic response of glioblastoma to TMZ and opened new avenues for optimizing the therapeutic effects of TMZ-based therapies.