Background Accumulating evidence demonstrates the oncogenic roles of lncRNA (long non-coding RNA) molecules in a wide variety of cancer types including glioma. Equally important, However, tumorigenic functions of lncRNA in glioma remain largely unclear. A recent study suggested lncRNA SNHG15 played a role for regulating angiogenesis in glioma but its role in the tumor microenvironment (TME) was not investigated. Methods First, we showed that SNHG15 was upregulated in GBM cells and associated with a poor prognosis for the patients of GBM using public databases. Next, we collected temozolomide sensitive (TMZ-S) and resistant (TMZ-R) clinical samples and demonstrated that co-culturing TMZ-R cells with HMC3 (microglial) cells promoted M2-polarization of HMC3 and the secretion of pro-GBM cytokines TGF-β and IL-6. Results Comparative qPCR analysis of TMZ-S and TMZ-R cells showed that a significantly higher level of SNHG15, coincidental with a higher level of Sox2, β-catenin, EGFR, and CDK6 in TMZ-R cells. Subsequently, using bioinformatics tool, a potential mechanistic route for SNHG15 to promote GBM tumorigenesis was by inhibiting tumor suppressor, miR-627-5p which leads to activation of CDK6. Gene-silencing technique was employed to demonstrate that suppression of SNHG15 indeed led to the suppression of GBM tumorigenesis, accompanied by an increase miR-627-5p and decreased its two oncogenic targets, CDK6 and SOX-2. In addition, SNHG15-silenced TMZ-R cells became significantly sensitive towards TMZ treatment and less capable of promoting M2-phenotype in the HMC3 microglial cells. We then evaluated the potential anti-GBM activity of CDK6 inhibitor, palbociclib, using TMZ-R PDX mouse models. Palbociclib treatment significantly reduced tumorigenesis in TMZ-R/HMC3 bearing mice and SNHG15 and CDK6 expression was significantly reduced while miR-627-5p level was increased. Additionally, palbociclib treatment appeared to overcome TMZ resistance as well as reduced M2 markers in HMC3 cells. Conclusion Together, we provided evidence supporting the usage of CDK6 inhibitor for TMZ-resistant GBM cases. Further investigation is warranted for the consideration of clinical trials. Graphical abstract Electronic supplementary material The online version of this article (10.1186/s13046-019-1371-0) contains supplementary material, which is available to authorized users.

Accumulating evidence indicates long noncoding RNAs (lncRNA) play a vital role in tumor progression. However, the role of linc00645-induced accelerated malignant behavior in glioblastoma (GBM) remains unknown. In the present study, linc00645 expression was significantly upregulated in GBM tissues and cell lines. High level of linc00645 was associated with poor overall survival in GBM patients. Knockdown of linc00645 suppressed the proliferation, stemness, migration, invasion, and reversed transforming growth factor (TGF)-β-induced motility of glioma cell lines. Furthermore, linc00645 directly interacted with miR-205-3p and upregulated of miR-205-3p impeded efficiently the increase of ZEB1 induced by linc00645 overexpression. Moreover, knockdown of linc00645 significantly suppressed the progression of glioma cells in vivo. miR-205-3p was a target of linc00645 and linc00645 modulates TGF-β-induced glioma cell migration and invasion via miR-205-3p. Taken together, our findings identified the linc00645/miR-205-3p/ZEB1 signaling axis as a key player in EMT of glioma cells triggered by TGF-β. These data elucidated that linc00645 plays an oncogenic role in glioma and it may serve as a prognostic biomarker and a potential therapeutic target for the treatment of glioma in humans.

Allicin is an extract purified from Allium sativum (garlic), and previous research has indicated that Allicin has an inhibitory effect on many kinds of tumor cells. The aim of the present study was to explore the anticancer activity of Allicin on human glioma cells and investigate the underlying mechanism. MTT and colony-formation assays were performed to detect glioma cell proliferation, and explore the effect of Allicin at various doses and time-points. The apoptosis of glioma cells was measured by fluorescence microscopy with Hoechst 33258 staining, and then flow cytometry was used to analyzed changes in glioma cell apoptosis. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were used to detect the effect of Allicin on the expression levels of Fas/Fas ligand (FasL), caspase‑3, B‑cell lymphoma 2 and Bcl‑2‑associated X protein. Allicin suppressed the proliferation and colony formation ability of U251 cells in a dose‑ and time‑dependent manner. A cytotoxic effect of Allicin was observed in glioma cells in a dose‑dependent manner. Changes in nuclear morphology were observed in U251 cells with Hoechst 33258 staining. The activity of caspases were significantly elevated and Fas/FasL expression levels were increased following treatment with Allicin, at both the mRNA and protein level. These results demonstrated that Allicin suppresses proliferation and induces glioma cell apoptosis in vitro. Both intrinsic mitochondrial and extrinsic Fas/FasL‑mediated pathways react in glioma cell after treating with Allicin, which then activate major apoptotic cascades. These results implicate Allicin as a novel antitumor agent in treating glioma.

Glioblastoma (GBM) is one of the most common and malignant types of primary cancer in the central nervous system; however, the clinical outcomes of patients with GBM remain poor. Circular RNAs (circRNAs) have been revealed to serve important roles in diverse biological processes, such as regulating cell proliferation, epithelial-mesenchymal transition and tumor development. However, the underlying biological function of circRNA filamin A (circFLNA) and its potential role in GBM remain to be determined. The present study aimed to identify differentially expressed circRNAs in GBM. Reverse transcription-quantitative PCR was used to analyze the expression levels of circFLNA. The results demonstrated that the expression levels of circFLNA were significantly upregulated in clinical GBM samples and GBM cells compared with adjacent healthy brain tissues and normal human astrocytes, respectively. The results of the Cell Counting Kit-8 and Transwell assays revealed that circFLNA knockdown significantly inhibited the proliferative and invasive abilities of GBM cell lines. Moreover, high circFLNA expression levels were associated with a worse prognosis in GBM. MicroRNA (miR)-199-3p was subsequently predicted to be target of circFLNA. The inhibitory effect of miR-199-3p on cell proliferation and invasion was partially reversed following circFLNA knockdown. In conclusion, the findings of the present study identified novel roles for circFLNA in GBM and indicated that the circFLNA/miR-199-3p signaling axis may serve an important role in GBM progression. Therefore, circFLNA may represent a novel target for the diagnosis and treatment of GBM.

Glioblastoma multiforme (GBM) is the most common and aggressive type of tumor of the primary nervous system. Treatment options for GBM include surgery, chemotherapy, and radiation therapy; however, the clinical outcomes are poor, with a high rate of recurrence. An increasing number of studies have shown that circular RNAs (circRNAs) serve important roles in several types of cancer. Gene Expression Omnibus (GEO) database was utilized to identify the differentially expressed cir-cRNAs and their biological functions. Then, we detected the circular RNA bifunctional apoptosis regulator (circBFAR) was significantly increased in three GEO datasets. However, the role of circBFAR has not been reported in GBM. In this study, the expression of circBFAR was significantly increased both in GBM tissues or cell lines and was negatively correlated with overall survival in patients with GBM. Knockdown of circBFAR inhibited proliferation and invasion both in vitro and in vivo. Increased expression of circBFAR resulted in a reduction of miR-548b expression in glioma cells. A luciferase reporter and RIP assay indicated that miR-548b was a direct target of circBFAR, and miR-548b may negatively regulate the expression of FoxM1. Rescue experiments showed that overexpression of FoxM1 could counter the effect of circBFAR silencing on the proliferation and invasion of glioma cell lines. Moreover, we identified that circBFAR regulates FoxM1 by

Background: Patients with non-small cell lung cancer (NSCLC) initially responding to tyrosine kinase inhibitors (TKIs) eventually develop resistance due to accumulating mutations in the EGFR and additional lesser investigated mechanisms such as the participation of the tumor microenvironment (TME). Methods: Here, we examined the potential for MET inhibitor capmatinib for the treatment of osimertinib-resistant NSCLCs and normalizing the TME. Results: We first established that HCC827 and H1975 cells showed increased resistance against osimertinib when co-cultured with CAFs isolated from osimertinib-resistant patients. Additionally, we showed that CAFs promoted epithelial-mesenchymal transition (EMT) and self-renewal ability in both HCC827 and H1975 cells. We subsequently found that both CAF-cultured HCC827 and H1975 showed a significantly higher expression of MET, Akt, Snail and IL-1β, which were associated with survival and inflammatory responses. These cells in turn, promoted the generation of CAFs from normal lung fibroblasts. Subsequently, we observed that the treatment of capmatinib resulted in the re-sensitization of CAF-co-cultured H1975 and HCC827 to osimertinib, in association with reduced EMT and self-renewal ability. MET-silencing experiment using siRNA supported the observations made with capmatinib while with a greater magnitude. MET-silenced cell exhibited a severely hindered expression of inflammatory markers, IL-1β and NF-κB; EMT markers, Snail and Vimentin, while increased E-cadherin. Finally, we demonstrated that the combination of capmatinib and osimertinib led to an increased tumor inhibition and significantly lower number of CAFs within the patient derived xenograft (PDX) model. Conclusion: Taken together, our findings suggested that an increased MET/Akt/Snail signaling was induced between the NSCLC cells and their TME (CAFs), resulting in osimertinib resistance. Suppression of this pathway by capmatinib may bypass the EGFR activating mutation and overcomes osimertinib resistance by targeting both tumor cells and CAFs.

Glioma is the most common type of primary brain tumor. Treatment options for recurrent gliomas include surgery, chemotherapy, and radiation therapy, but the clinical outcome is usually limited. In recent years, circular RNAs have been found to play a vital role in several human cancers. Gene Expression Omnibus database was utilized to verify the differentially expressed circRNAs. Then we detected that the expression of circular RNA circHECTD1 was significantly increased. The expression and function of circHECDT1 has not yet been reported in glioma. Then we confirmed that the level of circHECTD1 was significantly increased both in glioma tissues and cell lines, which is negatively correlated with the overall survival of patients. Knockdown of circHECTD1 inhibited proliferation and invasion in vitro, and also reduced the growth of tumor and prolonged the prognosis in vivo. Knockdown of circHECTD1 significantly elevated the miR‐296‐3p expression in LN229 and T98G cells. Luciferase reports and RNA immunoprecipitation data indicated that miR‐296‐3p was a direct target of circHECTD1 and that the miR‐296‐3p expression negatively regulated SLC10A7. Rescue experiments showed that the overexpression of SLC10A7 could impede the effects of circHECTD1 silencing on the proliferation and invasion of glioma cells. In this study, we identified that circHECTD1 regulates SLC10A7 by interacting with miR‐296‐3p in glioma cells. In conclusion, this study investigated a novel biomarker panel consisting of the circHECTD1/miR‐296‐3p/SLC10A7 axis, which is critical for glioma tumorigenesis and invasiveness and may represent a novel therapeutic target for intervening in glioma progression.

Increasing evidence indicates that glioma topographic location is linked to the cellular origin, molecular alterations and genetic profile. This research aims to (a) reveal the underlying mechanisms of tumor location predilection in glioblastoma multiforme (GBM) and lower-grade glioma (LGG) and (b) leverage glioma location features to predict prognosis. MRI images from 396 GBM and 190 LGG (115 astrocytoma and 75 oligodendroglioma) patients were standardized to construct frequency maps and analyzed by voxel-based lesion-symptom mapping. We then investigated the spatial correlation between glioma distribution with gene expression in healthy brains. We also evaluated transcriptomic differences in tumor tissue from predilection and nonpredilection sites. Furthermore, we quantitively characterized tumor anatomical localization and explored whether it was significantly related to overall survival. Finally, we employed a support vector machine to build a survival prediction model for GBM patients. GBMs exhibited a distinct location predilection from LGGs. GBMs were nearer to the subventricular zone and more likely to be localized to regions enriched with synaptic signaling, whereas astrocytoma and oligodendroglioma tended to occur in areas associated with the immune response. Synapse, neurotransmitters and calcium ion channel-related genes were all activated in GBM tissues coming from predilection regions. Furthermore, we characterized tumor location features in terms of a series of tumor-to-predilection distance metrics, which were able to predict GBM 1-year survival status with an accuracy of 0.71. These findings provide new perspectives on our understanding of tumor anatomic localization. The spatial features of glioma are of great value in individual therapy and prognosis prediction.