TAK-242 inhibits glioblastoma invasion, migration, and proneural-mesenchymal transition by inhibiting TLR4 signaling.

Resatorvid (TAK-242), a small-molecule inhibitor of Toll-like receptor 4 (TLR4), has the ability to cross the blood-brain barrier (BBB). In this study, we explored the role of TAK-242 on glioblastoma (GBM) invasion, migration, and proneural-mesenchymal transition (PMT). RNA sequencing (RNA-Seq) data and full clinical information of glioma patients were downloaded from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) cohorts and then analyzed using R language; patients were grouped based on proneural (PN) and mesenchymal (MES) subtypes. Bioinformatics analysis was used to detect the difference in survival and TLR4-pathway expression between these groups. Cell viability assay, wound-healing test, and transwell assay, as well as an intracranial xenotransplantation mice model, were used to assess the functional role of TAK-242 in GBM in vitro and in vivo. RNA-Seq, Western blot, and immunofluorescence were employed to investigate the possible mechanism. TLR4 expression in GBM was significantly higher than in normal brain tissue and upregulated the expression of MES marker genes. Moreover, TAK-242 inhibited GBM progression in vitro and in vivo via linking with PMT, which could be a novel treatment strategy for inhibiting GBM recurrence.

Suberanilohydroxamic acid (SAHA), a HDAC inhibitor, suppresses the effect of Treg cells by targeting the c-Myc/CCL1 pathway in glioma stem cells and improves PD-L1 blockade therapy.

PURPOSE: A strong immunosuppressive tumor microenvironment (TME) represents the major barrier responsible for the failure of current immunotherapy approaches in treating Glioblastoma Multiforme (GBM). Within the TME, the regulatory T cells (Tregs) exert immunosuppressive effects on CD8+ T cell - mediated anti-cancer immune killing. Consequently, targeting and inhibiting their immunosuppressive function emerges as an effective therapeutic strategy for GBM. The present study aimed to investigate the mechanisms and effects of Suberanilohydroxamic Acid (SAHA), a histone deacetylase inhibitor, on immunosuppressive Tregs. METHODS: The tumor-infiltrating immune cells in the immunocompetent GBM intracranial implanted xenograft mouse model were analyzed by immunohistochemistry and flow cytometry techniques. The mRNA expressions were assessed through the RT-qPCR method, while the related protein expressions were determined using western blot, ELISA, immunofluorescence (IF), and flow cytometry techniques. The relationship between c-Myc and C-C motif Chemokine Ligand 1 (CCL1) promotor was validated through a dual-luciferase reporter assay system and chromatin immunoprecipitation. RESULTS: SAHA suppressed effectively tumor growth and extended significantly overall survival in the immunocompetent GBM intracranial xenograft mouse model. Additionally, it promoted the infiltration of CD8+ T lymphocytes while suppressed the infiltration of CD4+ CD25+ Tregs. Furthermore, SAHA enhanced anti-PD-L1 immune therapy in the intracranial xenograft of mice. Mechanistically, SAHA exerted its effects by inhibiting histone deacetylase 2 (HDAC2), thereby suppressing the binding between c-Myc and the CCL1 promotor. CONCLUSION: SAHA inhibited the binding of c-Myc with the CCL1 promoter and then suppressed the transcription of CCL1.Additionally, it effectively blocked the interplay of CCL1-CCR8, resulting in reduced activity of Tregs and alleviation of tumor immunosuppression.

Metformin-induced reduction of CCR8 enhances the anti-tumor immune response of PD-1 immunotherapy in glioblastoma.

Immunotherapy strategies targeting the programmed cell death 1 (PD-1) in clinical treatments have shown limited success in controlling glioblastoma malignancies. Metformin exserts antitumor function, yet the underlying mechanisms remain unclear. Here, we investigated whether metformin could enhance the effectiveness of anti-PD-1 therapy by activating the immune system. Whether combination of an anti-PD-1 antibody or not, metformin significantly increased tumor-infiltrating CD4+ T cells while decreased regulatory T (Treg) cells in a mouse GBM model. Additionally, metformin reduced CC motif chemokine receptor CCR8 and elevated Interleukin 17 A (IL-17 A) expressions. Mechanistically, metformin reduces histone acetylation at the CCR8 promotor and inhibits CCR8 expression by upregulating AMP-activated protein kinase (AMPK)-activated sirtuin 2 (SIRT2). Metformin enhances the effectiveness of anti-PD-1 immunotherapy by reducing CCR8 expression on tumor-infiltrating Treg cells, suggesting that metformin has an antitumor effect by alleviating immunosuppression and promoting T cell-mediated immune response.

Retrospective analysis of 16 cases of lumbar hernia.

Background: Through a retrospective analysis of 16 cases of lumbar hernia, we discussed the anatomical basis, clinical manifestations, diagnosis, and treatment of this rare condition. Methods: We collected medical data of 15 patients with a primary lumbar hernia and one patient with a secondary lumbar hernia treated in the General Surgery Department of Wuxi No.2 People's Hospital between January 2008 and June 2021 and analysed their demographic, preoperative, and postoperative data. Results: All patients underwent elective surgery performed by the same treatment team for superior lumbar hernias. The median area of the hernia defect was 12 cm2. Fifteen patients underwent sublay repair, and one underwent onlay repair. The median operative time and blood loss were 48 min and 22 mL, respectively. The hernia contents were extraperitoneal fat in 15 patients and partial small intestine in one. The median visual analogue scale score on postoperative day 1 was 3. A postoperative drainage tube was placed in three cases but not used in 13. The median duration of hospital stay was 5 days. Postoperative incision infection occurred in one case. During the follow-up period, no postoperative complications, including haematoma, seroma, incision infection or rupture, recurrence, and chronic pain, occurred in the other 15 cases. Conclusion: Lumbar hernias are rare and can be safely and effectively treated by open tension-free repair.

Targeting EZH2 regulates the biological characteristics of glioma stem cells via the Notch1 pathway.

Glioma is the most common malignant brain tumor, and its behavior is closely related to the presence of glioma stem cells (GSCs). We found that the enhancer of zeste homolog 2 (EZH2) is highly expressed in glioma and that its expression is correlated with the prognosis of glioblastoma multiforme (GBM) in two databases: The Cancer Genome Atlas and the Chinese Glioma Genome Atlas. Additionally, EZH2 is known to regulate the stemness-associated gene expression, proliferation, and invasion ability of GSCs, which may be achieved through the activation of the STAT3 and Notch1 pathways. Furthermore, we demonstrated the effect of the EZH2-specific inhibitor GSK126 on GSCs; these results not only corroborate our hypothesis, but also provide a potential novel treatment approach for glioma.

Fractalkine Enhances Hematoma Resolution and Improves Neurological Function via CX3CR1/AMPK/PPARγ Pathway After GMH.

BACKGROUND: Hematoma clearance has been a proposed therapeutic strategy for hemorrhagic stroke. This study investigated the impact of CX3CR1 (CX3C chemokine receptor 1) activation mediated by r-FKN (recombinant fractalkine) on hematoma resolution, neuroinflammation, and the underlying mechanisms involving AMPK (AMP-activated protein kinase)/PPARγ (peroxisome proliferator-activated receptor gamma) pathway after experimental germinal matrix hemorrhage (GMH). METHODS: A total of 313 postnatal day 7 Sprague Dawley rat pups were used. GMH was induced using bacterial collagenase by a stereotactically guided infusion. r-FKN was administered intranasally at 1, 25, and 49 hours after GMH for short-term neurological evaluation. Long-term neurobehavioral tests (water maze, rotarod, and foot-fault test) were performed 24 to 28 days after GMH with the treatment of r-FKN once daily for 7 days. To elucidate the underlying mechanism, CX3CR1 CRISPR, or selective CX3CR1 inhibitor AZD8797, was administered intracerebroventricularly 24 hours preinduction of GMH. Selective inhibition of AMPK/PPARγ signaling in microglia via intracerebroventricularly delivery of liposome-encapsulated specific AMPK (Lipo-Dorsomorphin), PPARγ (Lipo-GW9662) inhibitor. Western blot, Immunofluorescence staining, Nissl staining, Hemoglobin assay, and ELISA assay were performed. RESULTS: The brain expression of FKN and CX3CR1 were elevated after GMH. FKN was expressed on both neurons and microglia, whereas CX3CR1 was mainly expressed on microglia after GMH. Intranasal administration of r-FKN improved the short- and long-term neurobehavioral deficits and promoted M2 microglia polarization, thereby attenuating neuroinflammation and enhancing hematoma clearance, which was accompanied by an increased ratio of p-AMPK (phosphorylation of AMPK)/AMPK, Nrf2 (nuclear factor erythroid 2-related factor 2), PPARγ, CD36 (cluster of differentiation 36), CD163 (hemoglobin scavenger receptor), CD206 (the mannose receptor), and IL (interleukin)-10 expression, and decreased CD68 (cluster of differentiation 68), IL-1ß, and TNF (tumor necrosis factor) α expression. The administration of CX3CR1 CRISPR or CX3CR1 inhibitor (AZD8797) abolished the protective effect of FKN. Furthermore, selective inhibition of microglial AMPK/PPARγ signaling abrogated the anti-inflammation effects of r-FKN after GMH. CONCLUSIONS: CX3CR1 activation by r-FKN promoted hematoma resolution, attenuated neuroinflammation, and neurological deficits partially through the AMPK/PPARγ signaling pathway, which promoted M1/M2 microglial polarization. Activating CX3CR1 by r-FKN may provide a promising therapeutic approach for treating patients with GMH.

G9a promotes immune suppression by targeting the Fbxw7/Notch pathway in glioma stem cells.

AIM: Immunotherapy for glioblastoma multiforme (GBM) is limited because of a strongly immunosuppressive tumor microenvironment (TME). Remodeling the immune TME is an effective strategy to eliminate GBM immunotherapy resistance. Glioma stem cells (GSCs) are inherently resistant to chemotherapy and radiotherapy and involved in immune evasion mechanism. This study aimed to investigate the effects of histone methyltransferases 2 (EHMT2 or G9a) on immunosuppressive TME and whether this effect was related to changes on cell stemness. METHODS: Tumor-infiltrating immune cells were analyzed by flow cytometry and immunohistochemistry in orthotopic implanted glioma mice model. The gene expressions were measured by RT-qPCR, western blot, immunofluorescence, and flow cytometry. Cell viability was detected by CCK-8, and cell apoptosis and cytotoxicity were detected by flow cytometry. The interaction of G9a and F-box and WD repeat domain containing 7 (Fbxw7) promotor was verified by dual-luciferase reporter assay and chromatin immunoprecipitation. RESULTS: Downregulation of G9a retarded tumor growth and extended survival in an immunocompetent glioma mouse model, promoted the filtration of IFN-γ + CD4+ and CD8+ T lymphocytes, and suppressed the filtration of PD-1+ CD4+ and CD8+ T lymphocytes, myeloid-derived suppressor cells (MDSCs) and M2-like macrophages in TME. G9a inhibition decreased PD-L1 and increased MHC-I expressions by inactivating Notch pathway companying stemness decrease in GSCs. Mechanistically, G9a bound to Fbxw7, a Notch suppressor, to inhibit gene transcription through H3K9me2 of Fbxw7 promotor. CONCLUSION: G9a promotes stemness characteristics through binding Fbxw7 promotor to inhibit Fbxw7 transcription in GSCs, forming an immunosuppressive TME, which provides novel treatment strategies for targeting GSCs in antitumor immunotherapy.

Heat shock protein 27 deficiency promotes ferrous ion absorption and enhances acyl-Coenzyme A synthetase long-chain family member 4 stability to promote glioblastoma cell ferroptosis.

BACKGROUND: Glioblastoma is one of the malignant tumors of the central nervous system with high lethality, high disability and low survival rate. Effective induction of its death is one of the existing challenges. In recent studies, heat shock protein 27 (HSP27) has been shown to be associated with ferroptosis; therefore, targeting HSP27 may be a potential therapeutic approach for GBM. METHODS: Immunohistochemistry and western blot analysis were used to detect the expression of HSP27 in GBM tissues. CCK8, plate clone formation assay, EdU proliferation assay for cell proliferation ability, PI, LDH release assay for cell viability. Reactive oxygen, iron levels, and mitochondrial potential for HSP27 silencing were assayed for ferrotosis in vitro. Western blotting and IP were used to verify the relationship between HSP27 and ACSL4. The effect of knockdown of HSP27 on tumor growth capacity was assessed in an intracranial xenograft model. RESULTS: HSP27 was significantly highly expressed in GBM. In vitro experiments, knockdown of HSP27 significantly induced ferroptosis in GBM cells. IP and western blot demonstrated a sumo-ization link between HSP27 and ACSL4. In vivo experiments, HSP27 deficiency retarded tumor growth rate by promoting ferroptosis. CONCLUSIONS: HSP27 deficiency promotes GBM ferroptosis. Targeting HSP27 may serve as a new direction for GBM treatment.

General Characteristics and Promotion Properties of Circular PLOD2 in Patients with Glioma.

BACKGROUND: Circular RNAs are closed endogenous RNAs that are involved in the progression of diverse tumors. Even with the most advanced combined treatments, patients with glioblastoma multiforme have a median survival time of <15 months. This study aimed to investigate the roles of circular PLOD2 (circPLOD2) in glioma tumorigenesis and tumor development and to clarify its tumor-promoting effects by bioinformatics analysis and molecular experiments. METHODS: To determine the characteristics of circPLOD2 expression, quantitative real-time polymerase chain reaction was conducted. Stable knockdown of circPLOD2 was implemented for functional assays. Cell Counting Kit-8 and colony formation assays were used to measure cell proliferation. Transwell assays and tube formation assays were used to evaluate cell invasion and angiogenesis abilities, respectively. An intracranial xenograft model was established to determine the function of circPLOD2 in vivo. Further biochemical and Western blot analyses were conducted to evaluate proteins associated with circPLOD2. RESULTS: circPLOD2 was upregulated in glioma tissues and cells. High expression of circPLOD2 was significantly associated with tumor size, World Health Organization grade, and molecular characteristics of glioma. circPLOD2 deregulation affected glioblastoma multiforme cell proliferation, invasion, and angiogenesis. Knockdown of circPLOD2 inhibited tumorigenesis in vivo. Further biochemical analysis showed that circPLOD2 was involved in oncogenic pathways and correlated with the expression of proteins related to proliferation, invasion, and angiogenesis. CONCLUSIONS: Our data indicate that circPLOD2 promotes glioma tumorigenesis and tumor development in vitro and in vivo and that suppressing circPLOD2 could be a novel therapeutic strategy for glioma.

Experimental study of selective MGMT peptides mimicking TMZ drug resistance in glioma.

Background: Glioblastoma (GBM) is a very frequent primary tumour in the cerebrospinal nervous system. Temozolomide (TMZ) is the first-line treatment for patients with GBM. However, some of GBM patients do not respond to TMZ. O6-methylguanine-DNA-methytransferase (MGMT) remains a major cause. In a previous study, we detected antibodies against MGMT peptides in patients with glioma, and five highly responsive autoantibodies anti-MGMT-02, anti-MGMT-04, anti-MGMT-07, anti-MGMT-10, and anti-MGMT-18 were identified that could be used to dynamically assess chemotherapy-resistant TMZ. Therefore, targeting MGMT peptides may be a potential therapeutic approach for GBM to fight TMZ resistance. Methods: First, MGMT-02 and MGMT-04 polypeptides with cell-penetrating peptides were designed and connected to FITC tracer for immunofluorescence localisation. CCK-8 and colony formation assay were performed to evaluate cell proliferation ability. Western blot and immunofluorescence analysis were used to detected the expression of apoptosis-related protein. Flow cytometry was used to detect the proportion of apoptosis in cells. TMZ-resistant effect of MGMT-02/04 peptides was assessed in intracranial xenograft nude mouse model. Results: We also found reduced apoptosis of cells treated with MGMT-02 and MGMT-04 peptides and TMZ compared with those treated separately with TMZ in vivo and in vitro experiences. Conclusion: The results of this study indicate that MGMT-02 and MGMT-04 peptides have a role in glioma resistance and that MGMT peptides may serve as a precise target for TMZ-resistant GBM.

[Retracted] miR­218­5p inhibits the stem cell properties and invasive ability of the A2B5+CD133­ subgroup of human glioma stem cells.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that Fig. 5 on p. 874 contained a series of DAPI panels within the figure that looked unexpectedly similar in appearance, with the similarities also evident in the second and 'Merge' data columns; moreover, of especial note, the similarities in the 'DAPI' panels for the Blank control experiments shown in Fig. 5C and D only affected a partial section of the data. In addition, the 'blank' and 'miR­control' panels in Fig. 6A also appeared to contain overlapping data. Independently of the issues that were raised by the interested reader, the authors themselves requested that their paper be retracted on account of having identified some problems with the presentation of various of the figures, and no longer being able to access their original data. The Editor of Oncology Reports has agreed that this paper should be retracted from the Journal, and apologizes to the readership for any inconvenience caused. [Oncology Reports 35: 869­877, 2016; DOI: 10.3892/or.2015.4418].

[Corrigendum] Downregulation of RNF138 inhibits cellular proliferation, migration, invasion and EMT in glioma cells via suppression of the Erk signaling pathway.

Following the publication of the above paper, during a routine examination of the raw data the authors noticed errors in Fig. 5 in the published version of the article. Essentially, in Fig. 5A on p. 3291, the western blot data for MMP2 (for the U87 cell line) did not match with the original data: An image from Fig. 7A (the western blotting data for Bcl2 in the U87 cell line had been erroneously selected during the process of assembling the figure); however, the authors were able to locate the original western blot data for MMP2 pertaining to Fig. 5A, and the corrected version of Fig. 5 is shown below. Note that these errors did not affect the overall conclusions reported in the study. All the authors agree to the publication of this corrigendum, and are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish it; furthermore, they apologize for any inconvenience caused to the readership of the Journal. [Oncology Reports 40: 3285­3296, 2018; DOI: 10.3892/or.2018.6744].

Anti-VEGFR2 monoclonal antibody(MSB0254) inhibits angiogenesis and tumor growth by blocking the signaling pathway mediated by VEGFR2 in glioblastoma.

Angiogenesis is a key physiological process that plays a key role in glioblastoma (GBM) progression and displays therapeutic resistance to antiangiogenic therapies. In this study, we aimed to identify whether vascular endothelial growth factor receptor 2(VEGFR2)monoclonal antibodies(mab)could inhibit tumorigenicity and the formation of vascular mimicry (VM) in GBM. The bioinformatic analysis from TCGA, CGGA, and TCPA databases and Immunohistochemistry (IHC) revealed that VEGFR2 is highly expressed in glioma tissues and results in a poor prognosis and is positively associated with VM markers (CD34 and PAS). The anti-VEGFR2 monoclonal antibodies(MSB0254)could inhibit the invasion, migration, and VM formation of U251 and primary glioma cells in vitro. In vivo, MSB0254 (m) could not only inhibit the growth of transplanted tumors of U251 and GL261 cells, but also significantly inhibit the expression of CD34, VEGFR2, Ki67, MMP2, MMP9 and reduce the expression of CD34/PAS and inhibit VM formation. The VEGFR2 monoclonal antibody could inhibit the angiogenesis and tumor growth of GBM by blocking the signaling pathway mediated by VEGFR2. It may become a new supplementary treatment for GBM.

Glioma Stem Cells Upregulate CD39 Expression to Escape Immune Response through SOX2 Modulation.

Ectonucleotidase CD39 hydrolyzing extracellular ATP (eATP) functions as a key modulator of immune response in the tumor microenvironment, yet the role of CD39 in contributing tumor stem cells in a more immunosuppressive microenvironment remains elusive. Here we report that the upregulation of CD39 is crucial for the decrease of extracellular ATP concentration around glioma stem cells (GSCs) to maintain an immunosuppressive microenvironment. Adriamycin (ADM) is able to promote the release of ATP, which recruits dendritic cells (DCs) to phagocytose GSCs. CD39 inhibition further increased extracellular ATP concentrations following ADM treatment and DCs phagocytosis. In addition, GSCs upregulated CD39 expression by SOX2-binding CD39 promotor. In mouse tumor models, the combination of ADM and CD39 blockade increased immune cell infiltration and reduced tumor size. These findings suggest that GSCs upregulate CD39 expression by their biological characteristics to maintain an immunosuppressive microenvironment, and CD39 inhibition supplies a favorable tumor microenvironment (TME) for immunotherapeutic intervention and enhances the immune response induced by chemotherapy.

Previously Unrecognized Nonreproducible Antibody-Probe Interactions.

Antibody-antigen (Ab-Ag) interactions are canonically described by a model that exclusively accommodates noninteraction (0) or reproducible interaction (RI) states, yet this model is inadequate to explain often-encountered nonreproducible signals. Here, by monitoring diverse experimental systems using a peptide-protein hybrid microarray, we observed that Ab-probe interactions comprise a substantial proportion of nonreproducible antibody-based results. This enabled our discovery and capacity to reliably identify nonreproducible Ab-probe interactions (NRIs), as well as our development of a powerful explanatory model ("0-NRI-RI-Hook four-state model") that is mAb concentration-dependent, regardless of specificity, which ultimately shows that both nonspecific interactions and NRIs are not predictable yet certain to happen. Our discoveries challenge the centrality of Ab-Ag interaction specificity data in serology and immunology.

Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion.

Diffuse invasion is the primary cause of treatment failure of glioblastoma (GBM). Previous studies on GBM invasion have long been forced to use the resected tumor mass cells. Here, a strategy to reliably isolate matching pairs of invasive (GBMINV ) and tumor core (GBMTC ) cells from the brains of 6 highly invasive patient-derived orthotopic models is described. Direct comparison of these GBMINV and GBMTC cells reveals a significantly elevated invasion capacity in GBMINV cells, detects 23/768 miRNAs over-expressed in the GBMINV cells (miRNAINV ) and 22/768 in the GBMTC cells (miRNATC ), respectively. Silencing the top 3 miRNAsINV (miR-126, miR-369-5p, miR-487b) successfully blocks invasion of GBMINV cells in vitro and in mouse brains. Integrated analysis with mRNA expression identifies miRNAINV target genes and discovers KCNA1 as the sole common computational target gene of which 3 inhibitors significantly suppress invasion in vitro. Furthermore, in vivo treatment with 4-aminopyridine (4-AP) effectively eliminates GBM invasion and significantly prolongs animal survival times (P = 0.035). The results highlight the power of spatial dissection of functionally accurate GBMINV and GBMTC cells in identifying novel drivers of GBM invasion and provide strong rationale to support the use of biologically accurate starting materials in understanding cancer invasion and metastasis.

USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4.

BACKGROUND: Glioblastomas (GBMs) are grade IV central nervous system tumors characterized by a poor prognosis and a short median overall survival. Effective induction of GBM cell death is difficult because the GBM cell population is genetically unstable, resistant to chemotherapy and highly angiogenic. In recent studies, ubiquitin-specific protease 7 (USP7) is shown to scavenge ubiquitin from oncogenic protein substrates, so effective inhibition of USP7 may be a potential key treatment for GBM. METHODS: Immunohistochemistry and western blotting were used to detect the expression of USP7 in GBM tissues. In vitro apoptosis assay of USP7 inhibition was performed by western blotting, immunofluorescence, and flow cytometry. Anti-apoptotic substrates of USP7 were defined by Co-IP and TMT proteomics. Western blotting and IP were used to verify the relationship between USP7 and its substrate. In an in vivo experiment using an intracranial xenograft model in nude mice was constructed to assess the therapeutic effect of target USP7. RESULTS: Immunohistochemistry and western blotting confirmed that USP7 was significantly upregulated in glioblastoma samples. In in vitro experiments, inhibition of USP7 in GBM induced significant apoptosis. Co-IP and TMT proteomics identified a key anti-apoptotic substrate of USP7, ADP-ribosylation factor 4 (ARF4). Western blotting and IP confirmed that USP7 interacted directly with ARF4 and catalyzed the removal of the K48-linked polyubiquitinated chain that binded to ARF4. In addition, in vivo experiments revealed that USP7 inhibition significantly suppressed tumor growth and promoted the expression of apoptotic genes. CONCLUSIONS: Targeted inhibition of USP7 enhances the ubiquitination of ARF4 and ultimately mediates the apoptosis of GBM cells. In a clinical sense, P5091 as a novel specific inhibitor of USP7 may be an effective approach for the treatment of GBM.

LncRNA-PVT1 indicates a poor prognosis and promotes angiogenesis via activating the HNF1B/EMT axis in glioma.

Recent studies identified that long non-coding RNAs (lncRNAs) exhibited critical roles in tumor migration and invasion. However, the roles of lncRNAs in glioma remain unclear. The aim of this study was to uncover the underlying mechanisms of glioma progression and provide potential therapeutic targets for its treatment in clinic. Our microarray study showed that lncRNA-PVT1 was significantly upregulated in glioma tissues and played an important role in cell proliferation, migration, invasion and angiogenesis. Our data showed that the expression of lncRNA-PVT1 was increased obviously and associated with advanced tumor stage, metastasis, invasion ability, and poor prognosis in glioma patients. Up-regulation of lncRNA-PVT1 was observed to promote glioma cells proliferation, and invasion abilities in vitro as well as tumor growth in vivo by regulating miR-1207-3p expression. Online software (TargetScan, miRDB and miR TarBase) were used to predict the regulating mechanisms of lncRNA-PVT1, miR-1207-3p and HNF1B, which were validated by dual-luciferase reporter gene system. In vivo tumor-bearing mice models were established to validate the cellular results. Therefore, we suggested that lncRNA-PVT1/miR-1207-3p/HNF1B axis might play critical roles in glioma progression, indicating that lncRNA-PVT1/miR-1207-3p/HNF1B signaling axis may serve as novel molecular targets for glioma prevention and treatment.