Potential Therapeutic Target For Glioma Research Articles

Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAR Gamma: A Potential Therapeutic Target in Gliomas.

In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two systems act in an opposite manner. This review focuses on the interplay between WNT/β-catenin signaling and PPAR-γ and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/β-catenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis, tumor growth, and angiogenesis. Activation of PPAR-γ agonists inhibits various signaling pathways such as the JAK/STAT, WNT/β-catenin, and PI3K/Akt pathways, which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin, and sulforaphane downregulate the WNT/β-catenin pathway through the upregulation of PPAR-γ and thus appear to provide an interesting therapeutic approach for gliomas. Temozolomide (TMZ) is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.

MAD2-p31comet axis deficiency reduces cell proliferation, migration and sensitivity of microtubule-interfering agents in glioma

Mitotic arrest deficient-like-1 (MAD2, also known as MAD2L1) is thought to be an important spindle assembly checkpoint protein, which ensures accurate chromosome segregation and is closely associated with poor prognosis in many cancer. As a MAD2 binding protein, p31comet counteracts the function of MAD2 and leads to mitotic checkpoint silence. In this study, we explore the function of MAD2-p31comet axis in malignant glioma cells. Our results showed that disruption of MAD2-p31comet axis by MAD2 knockdown or p31comet overexpression suppressed cell proliferation, survival and migration of glioma, indicating that MAD2-p31comet axis is required for maintaining glioma cells malignancy. It is noted that MAD2 depletion or p31comet overexpression reduced the sensitivity of glioma cells to microtubule-interfering agents paclitaxel and vinblastine, providing clinical guidance for application of such drugs. Taken together, our findings suggest that MAD2-p31comet axis may serve as a potential therapeutic target for glioma.

T-lymphokine-activated killer cell-originated protein kinase (TOPK) as a prognostic factor and a potential therapeutic target in glioma.

TOPK is overexpressed in various types of cancer and associated with poor outcomes in different types of cancer. In this study, we first found that the expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) was significantly higher in Grade III or Grade IV than that in Grade II in glioma (P = 0.007 and P < 0.001, respectively). Expression of TOPK was positively correlated with Ki67 (P < 0.001). Knockdown of TOPK significantly inhibited cell growth, colony formation and increased sensitivities to temozolomide (TMZ) in U-87 MG or U-251 cells, while TOPK overexpression promoted cell growth and colony formation in Hs 683 or A-172 cells. Glioma patients expressing high levels of TOPK have poor survival compared with those expressing low levels of TOPK in high-grade or low-grade gliomas (hazard ratio = 0.2995; 95% CI, 0.1262 to 0.7108; P = 0.0063 and hazard ratio = 0.1509; 95% CI, 0.05928 to 0.3842; P < 0.0001, respectively). The level of TOPK was low in TMZ-sensitive patients compared with TMZ-resistant patients (P = 0.0056). In TMZ-resistant population, patients expressing high TOPK have two months’ shorter survival time than those expressing low TOPK. Our findings demonstrated that TOPK might represent as a promising prognostic and predictive factor and potential therapeutic target for glioma.

Migfilin promotes migration and invasion in glioma by driving EGFR and MMP-2 signalings: A positive feedback loop regulation

Glioma is the most common type of primary brain tumors in the central nervous system (CNS). Migfilin occurs in human glioma and enhances cellular motility via the epidermal growth factor receptor (EGFR) pathway. However, the underlying molecular mechanism is not fully understood. In this study, we found that Migfilin promoted matrix metalloproteinase-2 (MMP-2) activity, and restrained the expression of tissue inhibitor of metalloproteinase 2 (TIMP2), which is an MMP-2 inhibitor. Functional and structural studies showed that the LIM1 domain of Migfilin was required for Migfilin-mediated TIMP2 expression inhibition and MMP-2 activity, and was also necessary in promoting cell motility. Furthermore, Migfilin-induced EGFR phosphorylation was greatly reduced by MMP-2 inhibitor (GM6001) or siRNA, while Migfilin-induced MMP-2 activation was also blocked by the EGFR inhibitor (AG1478) or siRNA. MMP-2 and EGFR inhibitors and their siRNAs can block Migfilin-induced migration and invasion, respectively. These results demonstrated that EGFR and MMP-2 signalings may form a positive feedback loop to enhance Migfilin-induced migration and invasion. Finally, we detected that the expression of Migfilin, EGFR phosphorylation (Tyr1173) and MMP-2 activity had a positive correlation in the clinical glioma sample. Taken together, these results suggest that Migfilin is a critical regulator in cellular motility by driving the EGFR-MMP-2 feedback loop, and may be considered as a potential therapeutic target in glioma.

Regulation of HOXA11-AS/miR-214-3p/EZH2 axis on the growth, migration and invasion of glioma cells

BackgroundGlioma is one of the most common and aggressive malignant tumors in central nervous system. Recently, long non-coding RNA (lncRNA) HOXA11-AS has been reported to be an oncogenic gene in multiple cancers. However, the molecular mechanisms of HOXA11-AS involved in cancer progression of human glioma remain unknown. Materials and methodsThe expression levels of HOXA11-AS in 45 paired primary glioma tissues and cell lines were examined by quantitative real-time PCR, and the correlation between HOXA11-AS expression and clinicopathologic characteristics of patients with glioma were analyzed. HOXA11-AS was knockdown in glioma cells by transfection with HOXA11-AS siRNA, and cell proliferation, migration and invasion were detected. The tumor growth of xenografts with HOXA11-AS knockdown glioma cells was also analyzed. ResultsThe expression levels of HOXA11-AS were significantly up-regulated in glioma tissues and cell lines compared with that in adjacent normal brain tissues and normal human astrocytes (NHA). High expression of HOXA11-AS was correlated with shorter overall survival in patients with glioma. Knockdown of HOXA11-AS inhibited glioma cell proliferation, migration and invasion in vitro, and tumor growth in vivo. In addition, we demonstrated that HOXA11-AS functioned as a competing endogenous RNA (ceRNA) for miR-214-3p, which in turn positively regulated the expression of its direct target EZH2. ConclusionsWe demonstrated that HOXA11-AS acted as an oncogenic lncRNA that promoted cell growth and metastasis of glioma through regulating miR-214-3p/EZH2 axis. These results suggested HOXA11-AS may serve as an efficient marker and a potential therapeutic target for glioma.

MiR-338 suppresses cell proliferation and invasion by targeting CTBP2 in glioma.

Previous studies indicated that microRNA-338-5p (miR-338-5p) functions as tumor suppressor in some cancer types including glioma. However, the clinical significance and biological function of miR-338-5p in glioma still need to be explored. We used quantitative real time PCR (qRT-PCR) to detect the miR-338-5p expression in the 44 cases of glioma tissues and adjacent normal tissues. In vitro, CCK8 cell proliferation, cell colony formation, transwell invasion assay and flow cytometry analysis were performed to explore the effects of miR-338-5p on cell proliferation, cell invasion and cell cycle distribution. Dual luciferase assay, qRT-PCR and western blot analysis were applied to validate CTBP2 was a direct target of miR-338-5p in glioma cells. we demonstrated that miR-338-5p was significantly lower expression in 44 glioma patients, compared with adjacent normal tissues. MiR-338-5p expression was significantly correlated with glioma grades and Karnofsky Performance Status in patients. We then validated that increased miR-338-5p significantly inhibited the cell proliferation, cell invasion and epithelial-mesenchymal transition (EMT) in vitro. Moreover, Dual luciferase assay results indicated that CTBP2 was direct target of miR-338-5p in glioma cells. Meanwhile, CTBP2 silencing can rescued the phenotype changes induced by miR-338-5p inhibitor on cell proliferation and invasion in glioma. Our results suggested that miR-338-5p acts as tumor suppressor and could be a potential therapeutic target for glioma.

Silencing Pre-B-cell leukemia homeobox 3 decreases the proliferation of human glioma cells in vitro and in vivo.

Among primary brain tumors, gliomas are the most common and most aggressive, with a poor prognosis and limited treatment options. Thus, it is essential to determine the mechanisms involved in glioma development to develop effective therapies for glioma patients. Pre-B-cell leukemia homeobox 3 (PBX3), a critical member of the PBX family, is frequently overexpressed in multiple human malignancies. However, the expression patterns and biological functions, as well as the involved molecular functions of PBX3 in human gliomas remain largely unknown. In this study, we demonstrate that PBX3 expression is increased in both human glioma tissues and cell lines compared with their normal counterparts. These results suggested that PBX3 might be involved in glioma progression. Thus, the role of PBX3 in glioma cell proliferation was investigated using genetic knockdown and overexpression methods. The results showed that PBX3 knockdown inhibited glioma cell proliferation and induced apoptosis, while PBX3 overexpression significantly promoted glioma cell proliferation. Mechanistically, we found that PBX3 promoted cell proliferation by modulating cell cycle progression. A xenograft LN229 model was used to confirm that PBX3 depletion decreased tumor growth in vivo. In summary, our findings reveal that PBX3 may be a potential therapeutic target in gliomas.

MicroRNA-409-3p Represses Glioma Cell Invasion and Proliferation by Targeting High-Mobility Group Nucleosome-Binding Domain 5

Emerging evidence has suggested that aberrantly expressed microRNAs (miRNAs) are associated with glioma development and progression. The aberrant expression of miR-409-3p has been reported in several human cancers. However, little is known about the function of miR-409-3p in gliomas. The aim of this study was to investigate the specific role and molecular mechanism of miR-409-3p in gliomas. In the present study, we found that miR-409-3p was downregulated in glioma tissue and cell lines. Overexpression of miR-409-3p inhibited glioma cell invasion and proliferation, whereas suppression of miR-409-3p promoted glioma cell invasion and proliferation. High-mobility group nucleosome-binding domain 5 (HMGN5), a well-known oncogene in gliomas, was identified as a functional target of miR-409-3p using bioinformatics, dual-luciferase reporter assay, real-time quantitative polymerase chain reaction, and Western blot analysis. Furthermore, miR-409-3p was found to regulate the expression of matrix metalloproteinase 2 and cyclin D1. Restoration of HMGN5 expression significantly reversed the inhibitory effects of miR-409-3p overexpression on glioma cell invasion and proliferation. Taken together, our results suggest that miR-409-3p inhibits glioma cell invasion and proliferation by targeting HMGN5, representing a potential therapeutic target for glioma.

MicroRNA-181b Inhibits Cellular Proliferation and Invasion of Glioma Cells via Targeting Sal-Like Protein 4.

MicroRNAs (miRs), a class of noncoding RNAs that are 18–25 nucleotides in length, are able to suppress gene expression by targeting complementary regions of mRNAs and inhibiting protein translation. Recently, miR-181b was found to play a suppressive role in glioma, but the regulatory mechanism of miR-181b in the malignant phenotypes of glioma cells remains largely unclear. In this study, we found that miR-181b was significantly downregulated in glioma tissues when compared with normal brain tissues, and decreased miR-181b levels were significantly associated with high-grade pathology and a poor prognosis for patients with glioma. Moreover, miR-181b was downregulated in glioma cell lines (U87, SHG44, U373, and U251) compared to normal astrocytes. Overexpression of miR-181b significantly decreased the proliferation, migration, and invasion of glioma U251 cells. Sal-like protein 4 (SALL4) was identified as a novel target gene of miR-181b in U251 cells. The expression of SALL4 was significantly upregulated in glioma tissues and cell lines, and an inverse correlation was observed between the miR-181b and SALL4 expression levels in glioma. Further investigation showed that the protein expression of SALL4 was negatively regulated by miR-181b in U251 cells. Knockdown of SALL4 significantly inhibited the proliferation, migration, and invasion of U251 cells, while overexpression of SALL4 effectively reversed the suppressive effects of miR-181b on these malignant phenotypes of U251 cells. In conclusion, our study demonstrates that miR-181b has a suppressive effect on the malignant phenotypes of glioma cells, at least partly, by directly targeting SALL4. Therefore, the miR-181b/SALL4 axis may become a potential therapeutic target for glioma.

GGNBP2 Suppresses the Proliferation, Invasion, and Migration of Human Glioma Cells.

Gliomas are the most common and aggressive type of primary adult brain tumors. Although GGNBP2 has previously been considered to be a tumor suppressor gene, little is known about the association between GGNBP2 and glioma. In this study, we clearly demonstrated that GGNBP2 was downexpressed in glioma tissues, and its downexpression is related to the pathological grade and overall survival of patients with gliomas. Overexpression of GGNBP2 suppressed the proliferation, migration, and invasion of glioma cells. Mechanistically, we demonstrated that the PI3K/Akt and Wnt/β-catenin signaling pathways were suppressed by GGNBP2 overexpression. In contrast, knockdown of GGNBP2 has precisely the opposite effect. Collectively, these data indicate that GGNBP2 shows tumor suppressive activity in human glioma cells and may stand out as a potential therapeutic target for glioma.

Somatostatin receptor 2A in gliomas: Association with oligodendrogliomas and favourable outcome.

Somatostatin receptor subtype 2A (SSTR2A) is a potential therapeutic target in gliomas. Data on SSTR2A expression in different glioma entities, however, is particularly conflicting. Our objective was to characterize SSTR2A status and explore its impact on survival in gliomas classified according to the specific molecular signatures of the updated WHO classification. In total, 184 glioma samples were retrospectively analyzed for SSTR2A expression using immunohistochemistry with monoclonal antibody UMB-1. Double staining with CD68 was used to exclude microglia and macrophages from analyses. SSTR2A staining intensity and its localization in tumor cells was evaluated and correlated with glioma entities and survival. Diagnoses included 101 glioblastomas (93 isocitrate dehydrogenase (IDH) -wildtype, 3 IDH-mutant, 5 not otherwise specified (NOS)), 60 astrocytomas (22 IDH-wildtype, 37 IDH-mutant, 1 NOS), and 23 oligodendrogliomas (19 IDH-mutant and 1p/19q-codeleted, 4 NOS). SSTR2A expression significantly associated with oligodendrogliomas (79% SSTR2A positive) compared to IDH-mutant or IDH-wildtype astrocytomas (27% and 23% SSTR2A positive, respectively), and especially glioblastomas of which only 13% were SSTR2A positive (p < 0.001, Fisher's exact test). The staining pattern in glioblastomas was patchy whereas more homogeneous membranous and cytoplasmic staining was detected in oligodendrogliomas. Positive SSTR2A was related to longer overall survival in grade II and III gliomas (HR 2.7, CI 1.2–5.8, p = 0.013). In conclusion, SSTR2A expression is infrequent in astrocytomas and negative in the majority of glioblastomas where it is of no prognostic significance. In contrast, oligodendrogliomas show intense membranous and cytoplasmic SSTR2A expression, which carries potential diagnostic, prognostic, and therapeutic value.

Down-regulation of MicroRNA-133 predicts poor overall survival and regulates the growth and invasive abilities in glioma

miRNAs were reported as oncogene or tumour suppressors in various cancers and played important roles in tumour development and progression. Dysregulated miR-133 has been reported in several cancers, however, the expression and biological function of miR-133 in glioma remained unclear. In this study, we found that miR-133 expression level was significantly decreased in glioma tissues and cell lines by RT-qPCR. Then miR-133 mimics were used to evaluate the effects of miR-133 on cell proliferation and invasion in vitro. We found that overexpressed miR-133 could significantly suppress cell growth, and invasion in U87 cells. Additionally, we found that forkhead box C1 (FOXC1) was overexpressed in glioma tissue and it was directly regulated by miR-133. Overall, this study is the first proof to demonstrate that miR-133 function as tumour suppressor in glioma and inhibit cell proliferation and invasioned by directly targeting FOXC1, implying miR-133 as a potential therapeutic target for glioma.

Overexpression of SCUBE2 Inhibits Proliferation, Migration, and Invasion in Glioma Cells.

Signal peptide CUB EGF-like domain-containing protein 2 (SCUBE2), a member of the SCUBE family of proteins, was recently found to play an important role in cancer development. However, little is known regarding its biological function in glioma. In the present study, we investigated the effect of SCUBE2 on glioma and explored its relevant mechanisms. The study showed that SCUBE2 had a low expression in glioma tissue and cell lines. SCUBE2 overexpression inhibited glioma cell proliferation in vitro and in vivo as well as suppressed glioma cell migration and invasion in vitro. Furthermore, we found that the Sonic hedgehog (Shh) signaling pathway was involved in the inhibitory effect of SCUBE2 overexpression on glioma cells. In light of the results obtained from our study, SCUBE2 may be regarded as a potential therapeutic target for glioma.

Upregulation of long noncoding RNA zinc finger antisense 1 enhances epithelial-mesenchymal transition in vitro and predicts poor prognosis in glioma.

Increasing evidence indicates that long noncoding RNAs play important roles in development and progression of various cancers. Zinc finger antisense 1 is a novel long noncoding RNA whose clinical significance, biological function, and underlying mechanism are still undetermined in glioma. In this study, we reported that zinc finger antisense 1 expression was markedly upregulated in glioma and tightly correlated with clinical stage. Moreover, patients with high zinc finger antisense 1 expression had shorter survival. Multivariate Cox regression analysis provided a clue that, probably, zinc finger antisense 1 level could serve as an independent prognostic factor for glioma. Functionally, zinc finger antisense 1 acted as an oncogene in glioma because its knockdown could promote apoptosis and significantly inhibit cell proliferation, migration, and invasion. Furthermore, zinc finger antisense 1 silencing could result in cell cycle arrest at the G0/G1 phase and correspondingly decrease the percentage of S phase cells in both U87 and U251 cell lines. Moreover, it was found that silenced zinc finger antisense 1 could impair migration and invasion by inhibiting the epithelial-mesenchymal transition through reducing the expression of MMP2, MMP9, N-cadherin, Integrin β1, ZEB1, Twist, and Snail as well as increasing E-cadherin level in glioma. Taken together, our data identified that zinc finger antisense 1 might act as a valuable prognostic biomarker and potential therapeutic target for glioma.

Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells

Overexpression of structural maintenance of chromosomes 4 (SMC4) has been reported to be involved in tumor cell growth, migration and invasion, and to be correlated with poor prognosis of cancer patient. However, its clinical significance and biological role in glioma remain unknown. Herein, we found that SMC4 expression at both mRNA and protein level was markedly increased in glioma cells and clinical tissues and that it correlated with poor prognosis. SMC4 overexpression markedly promoted the glioma cell proliferation rate and migration and invasive capability in vitro and in vivo, whereas SMC4 downregulation reduced it. Moreover, the transforming growth factor β (TGFβ)/Smad signaling pathway, which was activated in SMC4-transduced glioma cells and inhibited in SMC4-silenced glioma cells, contributed to SMC4-mediated glioma cell aggressiveness. Our results provide new insight into the oncofunction of SMC4 and the mechanism by which the TGFβ/Smad pathway is hyperactivated in gliomas, indicating that SMC4 is a valuable prognostic factor and a potential therapeutic target in gliomas.

Smoothened is a poor prognosis factor and a potential therapeutic target in glioma

Malignant gliomas are associated with a high mortality rate. Thus, there is an urgent need for the development of novel targeted therapeutics. Aberrant Hedgehog signaling has been directly linked to glioma. GDC-0449 is a novel small molecule inhibitor of Hedgehog signaling that blocks the activity of smoothened (Smo). In this study, we evaluated the in vitro and in vivo effects of the smoothened inhibitor GDC-0449 on cell proliferation in human gliomas. We found that high expression of smoothened in glioma is a predictor of short overall survival and poor patient outcome. Our data suggest that GDC-0449 significantly inhibits the proliferation of glioma cells by inducing cell cycle arrest at the G1 phase. Our results demonstrate that GDC-0449 can effectively inhibit the migration and invasion of glioma cells. Furthermore, GDC-0449 treatment significantly suppressed glioma cell xenograft tumorigenesis. Mechanistically, GDC-0449 treatment markedly decreases the expression levels of key Hedgehog pathway component genes (Shh, Patched-1, Patched-2, smoothened, Gli1 and Gli2). These results indicate that GDC-0449 works through targeting the Hedgehog pathway. Taken together, our study suggests that smoothened could be used as a prognostic marker and molecular therapeutic target for glioma.

Lentivirus‑mediated knockdown of chondroitin polymerizing factor inhibits glioma cell growth invitro.

Glioma is the most common primary tumor in the central nervous system, characterized by rapid progression, aggressive behavior, frequent recurrence and poor prognosis. In the present study we demonstrated that chondroitin polymerizing factor(CHPF) is highly expressed in human glioma tissues and 4glioma cell lines. To explore the role of CHPF in glioma, a lentiviral vector expressing CHPF shRNA was constructed and transfected into the glioma U251 cells, which stably downregulated the expression levels of the CHPF gene in U251 cells invitro. U251 cell proliferation inhibition rates were determined by MTT assay. The effect of survivin shRNA on U251 cell cycle distribution and cell apoptosis was determined by flow cytometry. Compared to the shRNA‑Ctrl group of cells, the shRNA-CHPF group of cells exhibited decreased proliferation and a significant increase in the proportion of cells in the G0/G1phase. In addition, we found that knockdown of the expression of CHPF increased apoptosis in glioma U251 cells. Therefore, our results confirmed that CHPF promotes growth and inhibits apoptosis in glioma U251 cells. Thus, by invivo and invitro data, the present study suggests that CHPF could be a new potential therapeutic target for glioma.

Low expression of microRNA-320b correlates with tumorigenesis and unfavorable prognosis in glioma.

Accumulating evidence demonstrates that dysregulated microRNAs(miRNAs) play a critical role in tumorigenesis and progression of various cancers. miR-320b, a member of miR‑320 family, was revealed downregulated in numerous human cancers, including nasopharyngeal carcinoma and colorectal cancer. However, the function of miR‑320b in human glioma remained poorly defined. In this study, we report that miR‑320b was lowly expressed in glioma tissues and cell lines in contrast with controls, being closely correlated with histological malignancy of glioma. Furthermore, patients with low expression of miR‑320b were associated with poor prognostic outcomes. Invitro functional assays indicated that overexpression of miR‑320b could markedly enhance cell apoptosis rate and suppress cell proliferation, migration and invasion. miR-320b mimic impaired cell cycle and metastasis through inhibiting the expression of G1/S transition key regulator CyclinD1 as well as decreasing the expression level of MMP2 and MMP9. Additionally, upregulation of miR‑320b could markedly promote apoptosis by increasing the level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggested that miR‑320b might serve as a novel prognostic marker and potential therapeutic target for glioma.

MicroRNA-361-5p inhibits epithelial-to-mesenchymal transition of glioma cells through targeting Twist1.

MicroRNA-361-5p (miR-361-5p) has been reported to be dysregulated in various human cancer types. However, the function of miR-361-5p in glioma remains unknown. In the present study, we aimed to investigate the biological functions of miR-361-5p in regulating glioma progression and the underlying molecular mechanism. We found that miR-361-5p was significantly decreased in glioma tissues and cell lines as detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Functional analysis revealed that miR-361-5p overexpression significantly inhibited glioma cell migration, invasion and epithelial-mesenchymal transition (EMT) whereas suppression of miR-361-5p showed opposite effects. Bioinformatic analysis showed that Twist1, a critical EMT inducer, was a predicted target of miR-361-5p which was validated by dual-luciferase reporter assay, RT-qPCR and western blot analysis. Further analysis indicated that miR-361-5p regulates the Twist1/Bmi-1 signaling axis. Rescue experiments showed that restoration of Twist1 expression significantly reversed the suppressive effect of miR-361-5p on cell migration, invasion and EMT. Taken together, the present study demonstrated an important role of miR-361-5p in glioma - which regulated the EMT of glioma cells by targeting and regulating Twist1. These findings provide novel insight into understanding the role and mechanism of miR-361-5p in regulating the biolo-gical behavior of glioma cells and suggest that miR-361-5p is a novel potential therapeutic target for glioma.

The inflammatory cytokine IL-22 promotes murine gliomas via proliferation.

Interleukin (IL)-22 is newly identified proinflammatory cytokine involved in the T helper (Th)17 and Th22 response. However, the possible role of IL-22 in glioma remains uncertain. The results of the present study demonstrated higher expression levels of IL-22 and the receptor IL-22BP in the brain of GL261 glioma-inoculation mice, suggesting the regulatory role of IL-22 in glioma. Injection of IL-22 increased the severity of glioma in vivo and higher expression levels of IL-6, IL-1β and tumor necrosis factor (TNF)-α were detected in the brain using ELISA following IL-22 injection. To elucidate the mechanism underlying the effects of IL-22, the present study aimed firstly to determine the expression levels of IL-22 receptor in a glioma cell line via reverse transcription quantitative polymerase chain reaction. IL-22 treatment significantly increased the expression levels of signal transducer and activator of transcription (STAT)3 and the mRNA expression levels of STAT6 compared with the vehicle control. These results suggested that IL-22 may activate the Janus kinase (JAK)/STAT signaling pathway in glioma. Furthermore, IL-22 positively regulated the proliferation of glioma, consistent with its role in vivo. Conversely, IL-22-deficient mice exhibited prolonged survival compared with wild-type (WT) mice, and the expression levels of inflammatory cytokines were decreased in the brain of IL-22 knock-out (KO) mice compared with WT mice. Concordant with these results, it was observed that IL-22-neutralising antibody was able to increase the survival of mice with glioma and attenuate the disease by significantly reducing the cytokine levels in the brain. In conclusion, the results of the present study demonstrated that expression levels of IL-22 in the brain of mice with glioma may enhance symptoms due to the increased cytokine production of IL-6, IL-1β and TNF-α; this is consistent with IL-6/JAK/STAT signalling activation in vitro. Decreasing the expression levels of IL-22, achieved either with IL-22-KO mice or IL-22-neutralising antibody demonstrated protective effects on glioma development. Therefore, IL-22 may serve as a potential therapeutic target for glioma.