Pan-cancer analysis of prognostic and immunological role of IL4I1 in human tumors: a bulk omics research and single cell sequencing validation.

BACKGROUND: Interleukin-4 inducible gene 1 (IL4I1) regulates tumor progression in numerous tumor types. However, its correlation with immune infiltration and prognosis of patients in a pan-cancer setting remains unclear. METHODS: Data from the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), UALCAN, Clinical Proteomic Tumor Analysis Consortium (CPTAC), Gene Expression Omnibus (GEO), cBioPortal, Cancer Single-cell State Atlas (CancerSEA), and Tumor IMmune Estimation Resource(TIMER) databases were used to evaluate IL4I1 expression, clinical features and prognostic effects, gene set enrichment, and correlation with immune cell infiltration, as well as the relationship between IL4I1 methylation and expression and survival prognosis. Correlations with 192 anticancer drugs were also analyzed. RESULTS: IL4I1 was significantly overexpressed in the majority of tumors, and the imbalance of IL4I1 was significantly correlated with overall survival and pathological stage. Moreover, total IL4I1 protein was increased in cancer. Therefore, IL4I1 may be used as a prognostic biomarker or protective factor in numerous types of cancer. The methylation level of IL4I1 may also be used as a prognostic marker. The functional enrichment of IL4I1 was closely related to the immunomodulatory pathway. In addition, the level of tumor-associated macrophage infiltration was positively correlated with the expression of IL4I1 in pan-cancerous tissues. scRNA-seq analysis suggested that IL4I1 differ significantly among different cells in the tumor microenvironment and was most enriched in macrophages. Various immune checkpoint genes were positively correlated with IL4I1 expression in most tumors. In addition, patients with high IL4I1 expression may be resistant to BMS-754807 and docetaxel, but sensitive to temozolomide. CONCLUSION: IL4I1 may play a role as promoter of cancer and prognostic indicator in patients. High expression of IL4I1 is associated with the state of tumor immunosuppression and may contribute to tumor-associated macrophage invasion. Therefore, IL4I1 may be a new therapeutic target for the treatment and prognosis of patients with cancer.

Identification of tryptophan metabolic gene-related subtypes, development of prognostic models, and characterization of tumor microenvironment infiltration in gliomas.

Background: Epigenetic regulation and immunotherapy of tumor microenvironment (TME) is a hot topic in recent years. However, the potential value of tryptophan metabolism genes in regulating TME and immunotherapy is still unclear. Materials and methods: A comprehensive study of glioma patients was carried out based on 40 tryptophan metabolic genes. Subsequently, these prognostic tryptophan metabolic genes are systematically associated with immunological characteristics and immunotherapy. A risk score model was constructed and verified in the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) cohorts to provide guidance for prognosis prediction and immunotherapy of glioma patients. Results: We described the changes of tryptophan metabolism genes in 966 glioma samples from genetic and transcriptional fields and evaluated their expression patterns from two independent data sets. We identified two different molecular subtypes and found that two subtypes were associated with clinicopathological features, prognosis, TME cell infiltration, and immune checkpoint blockers (ICBs). Then, four genes (IL4I1, CYP1A1, OGDHL, and ASMT) were screened out by univariate and multivariate cox regression analysis of tryptophan metabolism genes, and a risk score model for predicting the overall survival (OS) of glioma patients was constructed. And its predictive ability is verified using the CGGA database. At the same time, we verified the expression of IL4I1, CYP1A1, OGDHL, and ASMT four genes in glioma specimens and cell lines in GES4260 and GES15824. Therefore, we constructed a nomogram to improve the clinical applicability of the risk assessment model. The high risk score group, characterized by increased TMB and immune cell infiltration, was also sensitive to temozolomide immunotherapy. Our comprehensive analysis of tryptophan metabolic genes in gliomas shows that they play a potential role in tumor immune stromal microenvironment, clinicopathological features, and prognosis. Conclusion: Tryptophan metabolism genes play an indispensable role in the complexity, diversity, and prognosis of TME. This risk score model based on tryptophan metabolism gene is a new predictor of clinical prognosis and immunotherapy response of glioma, and guides a more appropriate immunotherapy strategy for glioma patients.

PRLHR Immune Genes Associated With Tumor Mutation Burden can be Used as Prognostic Markers in Patients With Gliomas.

Tumor mutation burden (TMB) is a useful biomarker for predicting the prognosis and efficacy of immune checkpoint inhibitor (ICIs). In this study, we aimed to explore the prognostic value of TMB and TMB-related PRLHR immune genes as prognostic markers in patients with gliomas. We downloaded MAF files, RNA-seq data, and clinical information from the Cancer Genome Atlas (TCGA) database. The TMB of glioma was calculated and its correlation with clinical features and prognosis was analyzed. We found that TMB was statistically correlated with the grade and age of patients with gliomas. Kaplan-Meier curve analysis showed that low TMB was associated with better clinical outcome in patients with gliomas. Additionally, a predictive model based on five HUB genes (FABP5, VEGFA, SAA1, ADM, and PRLHR) was constructed to predict OS in patients with gliomas. Receiver operating characteristic curve analysis shows that the model is reliable in predicting the risk of survival and prognosis. Immune microenvironment analysis revealed a correlation between TMB and infiltrating immune cells. The clinical-related immune gene, PRLHR, can be used as an independent prognostic factor for patients with brain glioma, and it is negatively correlated with the grade of glioma and age of patients with glioma. We found that the higher the tumor grade and the older the age, the lower the PRLHR expression, which was verified by CGGA database and independent experimental data. These results suggest that PRLHR may be a tumor suppressor for the progression of glioma and might provide a new therapeutic target for the treatment and improvement of survival rate in patients with glioma.

MicroRNA-25 promotes cell proliferation, migration and invasion in glioma by directly targeting cell adhesion molecule 2.

Numerous microRNAs (miRNAs/miRs) have been demonstrated to serve oncogenic or suppressive roles in glioma. Exploration of the underlying molecular mechanism of miRNAs in the development and progression of glioma is beneficial for the identification of novel therapeutic targets. In the present study, the function of miR-25 in glioma progression, as well as its underlying mechanism, were investigated. It was determined that miR-25 was significantly upregulated in glioma tissues and cell lines compared with normal brain tissues and cells, respectively. Furthermore, high expression levels of miR-25 were associated with an advanced clinical stage. The knockdown of miR-25 expression significantly reduced glioma cell proliferation, migration and invasion. Cell adhesion molecule 2 (CADM2) was identified as a direct target of miR-25 in glioma cells. Moreover, CADM2 expression level was significantly downregulated and inversely correlated with miR-25 expression level in glioma tissues, indicating that the expression of CADM2 was negatively regulated by miR-25. The inhibition of CADM2 expression counteracted the effects on glioma cell proliferation, migration and invasion caused by miR-25 downregulation. Furthermore, CADM2 knockdown considerably promoted the proliferation and migration of glioma cells. In summary, the present study demonstrated that miR-25 was significantly upregulated in glioma and that it promoted glioma cell proliferation, migration and invasion, at least partially, by directly targeting CADM2. These findings expanded the understanding of the molecular mechanism that underlies glioma progression.

Omics- and Pharmacogenomic Evidence for the Prognostic, Regulatory, and Immune-Related Roles of PBK in a Pan-Cancer Cohort.

PDZ-binding kinase (PBK) is known to regulate tumor progression in some cancer types. However, its relationship to immune cell infiltration and prognosis in different cancers is unclear. This was investigated in the present study by analyzing data from TCGA, GEO, GETx, TIMER, CPTAC, GEPIA2, cBioPortal, GSCALite, PROGNOSCAN, PharmacoDB, STRING, and ENCORI databases. PBK was overexpressed in most tumors including adenocortical carcinoma (hazard ratio [HR] = 2.178, p < 0.001), kidney renal clear cell carcinoma (KIRC; HR = 1.907, p < 0.001), kidney renal papillary cell carcinoma (HR = 3.024, p < 0.001), and lung adenocarcinoma (HR = 1.255, p < 0.001), in which it was associated with poor overall survival and advanced pathologic stage. PBK methylation level was a prognostic marker in thyroid carcinoma (THCA). PBK expression was positively correlated with the levels of BIRC5, CCNB1, CDC20, CDK1, DLGAP5, MAD2L1, MELK, PLK1, TOP2A, and TTK in 32 tumor types; and with the levels of the transcription factors E2F1 and MYC, which regulate apoptosis, the cell cycle, cell proliferation and invasion, tumorigenesis, and metastasis. It was also negatively regulated by the microRNAs hsa-miR-101-5p, hsa-miR-145-5p, and hsa-miR-5694. PBK expression in KIRC, liver hepatocellular carcinoma, THCA, and thymoma was positively correlated with the infiltration of immune cells including B cells, CD4+T cells, CD8+ T cells, macrophages, monocytes, and neutrophils. The results of the functional enrichment analysis suggested that PBK and related genes contribute to tumor development via cell cycle regulation. We also identified 20 drugs that potentially inhibit PBK expression. Thus, PBK is associated with survival outcome in a variety of cancers and may promote tumor development and progression by increasing immune cell infiltration into the tumor microenvironment. These findings indicate that PBK is a potential therapeutic target and has prognostic value in cancer treatment.

CircRNA NALCN acts as an miR-493-3p sponge to regulate PTEN expression and inhibit glioma progression.

BACKGROUND: An increasing number of studies have shown that circular RNAs (circRNAs) play important roles in the regulation of tumor progression. Therefore, we explored the expression characteristics, function, and related mechanism of the newly identified circNALCN in glioma. METHODS: RNA sequencing was used to analyze the expression profiles of circRNAs in brain tissue from five glioma cases and four normal controls. Quantitative real-time polymerase chain reaction was implemented to examine the levels of circNALCN, miR-493-3p, and phosphatase and tensin homolog (PTEN). Cell counting kit 8 assays were performed to analyze cell proliferation, and cell migration was assessed by the wound healing test and Transwell assay. Dual-luciferase reporter, fluorescence in situ hybridization, and RNA pulldown assays were performed to confirm the role of circNALCN as an miR-493-3p sponge, weakening the inhibitory effect of miR-493-3p on target PTEN expression. RESULTS: The downregulated expression of circNALCN was observed in both glioma tissues and cell lines. CircNALCN expression was negatively correlated with World Health Organization grade and overall survival in patients with glioma. Functionally, the overexpression of circNALCN significantly inhibited the proliferation and migration of glioma cells, whereas miR-493-3p mimics counteracted these effects. The mechanistic analysis demonstrated that circNALCN acted as a competing endogenous RNA for miR-493-3p to relieve the repressive effects of miR-493-3p on its target, PTEN, suppressing glioma tumorigenesis. CONCLUSIONS: CircNALCN inhibits the progression of glioma through the miR-493-3p/PTEN axis, providing a developable biomarker and therapeutic target for glioma patients.

Successfully disposal of an acute MCA occlusion by Onyx during AVM embolism.

Purpose: To report a rare complication that Onyx gel blocked the MCA trunk and branches unexpectedly during AVM embolism and our strategy to rescue. Material and methods: A 16 years old otherwise healthy girl hold a left side Spetzler - Martin grade III fronto-temporal AVM, during embolization, the L-MCA and its branches were blocked by Onyx completely, the patient was transferred to the operating room to extract the Onyx gel immediately. Result: After totally 10 arterotomies, all the Onyx gel were removed. 8 hours after occlusion, all arteries were then seen to pulsate. Conclusion: Iatrogenic MCA full-length acute occlusion is a rare and severe complication during AVM embolism. Carefully identify the feeding arteries, micro-catheter angiography before Onyx gel injection and balloon-assisted embolism could probably prevent it. Surgical operation to extract onyx gel and re-canalize MCA was recommended, AVM should be resect if possible.

miR-25-3p promotes glioma cell proliferation and migration by targeting FBXW7 and DKK3.

MicroRNAs (miRs) serve important roles in glioma. However, the underlying molecular mechanism of miR-25 in glioma progression remains largely unknown; therefore, it was investigated in the present study. RT-qPCR analysis revealed that miR-25 expression levels were markedly increased in human glioma tissue and glioma cell lines compared with normal brain tissues and normal human astrocytes, respectively. miR-25 upregulation exhibited an association with glioma progression, and the knockdown of miR-25 significantly inhibited glioma cell proliferation and migration. F-box and WD repeat domain containing 7 (FBXW7) and dickkopf WNT signaling pathway inhibitor 3 (DKK3) were identified as target genes of miR-25. FBXW7 and DKK3 expression levels were significantly downregulated in glioma tissue samples compared with normal brain tissue, and their expression levels were negatively regulated by miR-25 expression in glioma cells. Furthermore, inhibition of FBXW7 and DKK3 expression suppressed the miR-25-induced effects on glioma cell proliferation and migration. The findings of the present study suggest that miR-25 may promote glioma cell proliferation and migration by inhibiting the expression of FBXW7 and DKK3. Therefore, miR-25 may serve as a promising molecular target for the treatment of glioma.

Epigenetically controlled Six3 expression regulates glioblastoma cell proliferation and invasion alongside modulating the activation levels of WNT pathway members.

Glioma is the most common primary brain tumor in adults. Six3 is a human homologue of the highly conserved sine oculis gene family and essential transcription regulatory factor in process of eye and fetal forebrain development. However, little is known about the role of Six3 in human tumorigenesis. The aim of this study is to investigate the methylation/expression of Six3 and reveal its function and action mechanism in glioma. Our results showed that Six3 was down-regulated in human glioma tissues and human glioma SHG-44, U251, SF126 and U373-MG cells compared with the normal tissues. And the down-regulation of Six3 was associated with the methylation of its promoter. Glioma U251 cells lacked endogenous Six3. Treatment with demethylating agent (5-aza-2'-deoxycytidine) or exogenous expression of Six3 restored Six3 production and resulted in suppression of cell cycle G1/S transition, proliferation and invasion and down-regulation of the expression of Wnt1, p-GSK3-ß, ß-catenin and cyclin D1 in glioma U251 cells. However, knockdown of Six3 in SHG-44 cells, which have relative higher baseline level of Six3, resulted in an opposite action. These results demonstrate that Six3 silence or loss in glioma is induced by its promoter hypermethylation and Six3 down-regulation contributes to proliferation and invasion of glioma. And this process is involved in activation of Wnt/ß-catenin pathway. Six3 play a suppressor role in the initiation and progression of human glioma and potentially serve as a target for the diagnosis and treatment of human glioma.

miRNA-429 Inhibits Astrocytoma Proliferation and Invasion by Targeting BMI1.

Glioblastoma multiforme (GBM), the most common primary brain cancer in adults, is usually the most lethal type of brain tumor. MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules that deeply involves with the regulation of gene expression and cellular processes, including proliferation, apoptosis, migration and invasion. The objective of the study is to investigate the effect of miRNA-429 on human glioblastoma tissues and cell lines. miRNA-429 expressions in human glioblastoma, normal brain tissue samples, and human malignant glioma cell lines (U87, U251 and LN229) were compared using reverse transcription-quantitative PCR and western blot methods. U251 cell lines were transfected with miRNA-429 mimics, and then the effects of miRNA-429 on cell proliferation and invasion were investigated by CCK8 and Transwell invasion assay, respectively. It was found that miRNA-429 expression was significantly reduced in the examined Glioblastoma samples and human glioma cell lines. Overexpression of miRNA-429 inhibited Glioblastoma cell proliferation and invasion. Additionally, the present study also showed that BMI1 was a functional target of miRNA-429. Overexpression of BMI1 undermined the inhibition effect of miRNA-429 in glioblastoma and U251 cell lines. The current study demonstrated that miRNA-429, as a tumor suppressor gene, was capable of negatively regulating the expression of BMI1 in U251 cells.

miR-25 promotes glioblastoma cell proliferation and invasion by directly targeting NEFL.

Glioblastoma multiforme (GBM) is the most malignant and common brain tumor; it is aggressive growth pattern means that GBM patients face a poor prognosis even when receiving the best available treatment modalities. In recent years, an increasing number of reports suggest that the discovery of microRNAs (miRNAs) might provide a novel therapeutic target for human cancers, including GBM. One miRNA in particular, microRNA-25 (miR-25), is overexpressed in several cancers, wherein accumulating evidence indicates that it functions as an oncogene. However, the function of miR-25 in GBM has not been totally elucidated. In this study, we demonstrated that miR-25 was significantly up-regulated in astrocytoma tissues and glioblastoma cell lines. In vitro studies further demonstrated that overexpressed miR-25 was able to promote, while its antisense oligos inhibited cell proliferation and invasion in U251 cells. Moreover, we identified neurofilament light polypeptide (NEFL) as a novel target molecule of miR-25. Also of note was the fact that NEFL was down-regulated with increased levels of miR-25 expression in human astrocytoma clinical specimens. In addition, via the mTOR signaling pathway, NEFL-siRNA could significantly attenuate the inhibitory effects of knockdown miR-25 on the proliferation and invasion of U251 cells. Overall, our results showed an important role for miR-25 in regulating NEFL expression in GBM, and suggest that miR-25 could be a potential target for GBM treatment.

Endothelin B receptor expression in human astrocytoma: association with clinicopathological variables and survival outcomes.

The endothelin (ET) axis has been implicated in astrocytoma growth and progression. Selective ETB receptor antagonists blocked proliferation and induced apoptosis in astrocytoma cell lines, suggesting that the ETB receptor could be a therapeutic target for astrocytomas. In the present study, we explored the association of the ETB receptor expression with clinicopathological variables and the prognosis of human astrocytomas, by examining the ETB receptor expression and Ki-67 staining in 71 surgically resected astrocytomas with immunohistochemistry. High expression of the ETB receptor was significantly associated with high grade of astrocytomas (p < .0001) and high Ki-67 labeling index (LI; p < .0001). Kaplan-Meier survival analysis showed that the ETB receptor high expression group had significantly shorter disease-free survival (DFS) and overall survival (OS) rates than the low expression group (p < .001). Multivariate analysis with the Cox's proportional hazards model revealed that high expression of the ETB receptor, high WHO grade, and high Ki-67 LI were independent factors for shorter DFS and OS (p < .05 for each comparison). In conclusion, high expression of the ETB receptor is closely associated with high malignancy and poor prognosis of human astrocytomas, which suggests that the ETB receptor could be a promising therapeutic target for astrocytomas, particularly high-grade astrocytomas.

[Neuroendoscopy for treatment of multilocular brain abscess in children].

OBJECTIVE: Multilocular brain abscess in children is a serious neurosurgical emergency and remains a serious, life-threatening disease. This study evaluated the role of neuroendoscopy in treating multilocular brain abscess in children. METHODS: Between January 2002 and June 2007, 16 children with multilocular brain abscess underwent an operation using a pure endoscopic procedure. RESULTS: Increased intracranial pressure was relieved after operation in the 16 patients. CT/MRI after operation showed the abscess cavities disappeared and only the residual abscess walls existed in the 16 patients. Fourteen patients were followed up for 6 months to 5 years after surgery. Abscess walls disappeared in 13 patients and abscess recurred only in 1 patient. CONCLUSIONS: Neuroendoscopy for treatment of multilocular brain abscess is safe and effective in children.

[Clinical significance of the expression of the RCAS1 mRNA and protein in astrocytic tumors].

OBJECTIVE: To determine the mRNA and protein expressions of RCAS1 in human astrocytic tumors, and to explore the relation between their expression and the genesis and development of tumor. METHODS: The RCAS1 mRNA expression in human astrocytic tumors was evaluated by RT-PCR, and the RCAS1 protein expression was studied by immunohistochemical staining. RESULTS: The quantities of RCAS1 mRNA expression between diffusive astrocytoma(Grade II) and anaplastic astrocytoma(Grade III), anaplastic astrocytoma and glioblastoma(Grade IV) were significantly different(P<0.05), while the expression scores of RCAS1 protein were different only between the anaplastic astrocytoma and glioblastoma(P<0.01). RCAS1 protein expression was positively correlated with the tumor grade (r=0.573,P<0.001). The RCAS1 protein was not detected in normal brain tissues by immunohistochemical staining. CONCLUSION: The RCAS1 expression is related to the histological grade of astrocytic tumor. In astrocytic tumors, the RCAS1 expression is regulated transcriptionally and posttranscriptionally.