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CHI3L2 Is a Novel Prognostic Biomarker and Correlated With Immune Infiltrates in Gliomas.

ABSTRACT: CHI3L2 (Chitinase-3-Like Protein 2) is a member of chitinase-like proteins (CLPs), which belong to the glycoside hydrolase 18 family. Its homologous gene, CHI3L1, has been extensively studied in various tumors and has been shown to be related to immune infiltration in breast cancer and glioblastoma. High CHI3L2 expression was reported to be associated with poor prognosis in breast cancer and renal cell carcinoma. However, the prognostic significance of CHI3L2 in glioma and its correlation between immune infiltration remains unclear. In this study, we examined 288 glioma samples by immunohistochemistry to find that CHI3L2 is expressed in tumor cells and macrophages in glioma tissues and highly expressed in glioblastoma and IDH wild-type gliomas. Relationships between CHI3L2 expression and clinical features (grade, age, Ki67 index, P53, PHH3 (mitotic figures), ATRX, TERTp, MGMTp, IDH, and 1p/19q co-deleted status) were evaluated. Kaplan-Meier survival was conducted to show high CHI3L2 expression in tumor cells (TC) and macrophage cells (MC) indicated poor prognosis in diffusely infiltrating glioma (DIG), lower-grade glioma (LGG), and IDH wild-type gliomas (IDH-wt). The overall survival time was higher in patients with dual-low CHI3L2 expression in TC and MC compared to those in patients with non-dual CHI3L2 expression and dual high expression in DIG and IDH wild-type gliomas. By univariate and multivariate analysis, we found that high CHI3L2 expression in tumor cells was an independent unfavorable prognostic factor in glioma patients. Moreover, we used two datasets (TCGA and CGGA) to verify the results of our study and explore the potential functional role of CHI3L2 by GO and KEGG analyses in gliomas. TIMER platform analysis indicated CHI3L2 expression was closely related to diverse marker genes of tumor immune infiltrating cells, including monocytes, TAMs, M1 macrophages, M2 macrophages, TGFβ1+ Treg and T cell exhaustion in GBM and LGG. Western Blot validated CHI3L2 is expressed in glioma cells and microglia cells. The results of flow cytometry showed that CHI3L2 induces the apoptosis of CD8+ T cells. In conclusion, these results demonstrate CHI3L2 is related to poor prognosis and immune infiltrates in gliomas, suggesting it may serve as a promising prognostic biomarker and represent a new target for glioma patients.

SUBMITTER: Liu L

PROVIDER: S-EPMC8084183 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: UBASH3B (STS1) is an important gene that negatively regulates T-cell receptor signaling in activated T-lymphocytes that involved in cancers. However, the function of UBASH3B in prostate cancer (PCa) and the correlation between UBASH3B and tumor-infiltrating immune cells still remain unclear. Methods: Real-time PCR and immunohistochemistry were applied to detect mRNA and protein expression of UBASH3B in PCa patients and benign prostate hyperplasia patients (BPH). Clinical features of patients with PCa were recorded and Kaplan Meier curve was subsequently plotted. Based on mRNA expression of UBASH3B, patients with PCa from TCGA database were divided into low-UBASH3B-expression group and high-UBASH3B-expression group for construct lncRNA-miRNA-mRNA network and analyzing GO and KEGG pathways. Single gene analysis method was performed by using GSEA to interpret gene expression data in PCa. The PPI network was constructed using STRING and the correlation between UBASH3B and tumor-infiltrating immune cells was analyzed by TIMER and CIBERSORT. Results: The mRNA and protein expression of UBASH3B were upregulated in PCa. The abundant expression of UBASH3B is associated with poor prognosis in PCa. The subnetwork of UBASH3B contains three lncRNAs (MIAT, LINC01297, MYLK-AS1) and four miRNAs (hsa-miR-200a-3p, hsa-miR-455-5p, hsa-miR-192-5p, hsamiR- 215-5P). The mRNA expression of UBASH3B was involved in 28 KEGG pathways. GSEA analysis showed that 18 hallmark gene sets were significantly enriched in high-UBASH3B-expression, whereas 1 gene set was enriched in low-UBASH3B-expression. PPI network revealed a tightly interaction between UBASH3B and LCP2 (an immune related gene). TIMER and CIBERSORT database indicated that UBASH3B was correlated with 11 types of tumor-infiltrating immune cells (naïve B cell, memory B cells, resting CD4+ memory T cell, activated CD4+ memory T cell, regulatory T cell, activated NK cell, M2 macrophages, resting dendritic cells, activated dendritic cells, resting mast cells, neutrophils). Conclusions: In conclusion, UBASH3B may be a novel potential prognostic biomarker and is associated with tumor-infiltrating immune cells in tumor microenvironment, suggesting UBASH3B as a potential target for future treatment of PCa.

Project description:Inhibin subunit beta B (INHBB) is a potential prognostic biomarker for a variety of cancers. However, its role in gastric cancer (GC) remains elusive. The differential expression data of INHBB in tumor and normal tissues were extracted from several databases and genetic alterations of INHBB were assessed by cBioPortal. Kaplan-Meier analysis was used to evaluate the survival rate of patients with GC with INHBB and association with clinical features in GC. Cox regression analysis was used to explore the prognostic value of clinical indicators and INHBB in GC, and a nomogram prognostic model was established. In addition, the predictive validity of the nomogram model was assessed by time-depended receiver operating characteristic (ROC) and calibration curves. Functional enrichment analyses were conducted to functionally annotate INHBB. Notably, we found that the quantitative assessment of immune cell subpopulation infiltration correlated with INHBB expression. INHBB expression is upregulated in GC and is correlated with several clinical features including prognostic indicators and a histological type. Genetic alterations were observed in INHBB, its DNA methylation level was negatively correlated with INHBB expression. High INHBB expression is associated with a poor prognosis and is an independent risk factor for prognosis in GC, along with age and residual tumor. The nomogram model showed a good prediction ability and was validated by time-depended ROC and calibration curves. Functional enrichment analysis indicated that INHBB-associated genes were enriched in tumor microenvironment Gene Ontology (GO) terms and were correlated with tumor-associated pathways. INHBB has a regulatory function in immune cell infiltration, especially macrophage infiltration in GC. Specifically, patients with GC with high INHBB expression and high macrophage infiltration have a worse prognosis. INHBB expression was negatively correlated with the expression of chemokines/chemokine receptors and plays a regulatory role in immunoinhibitor/immunostimulator-involved pathways. INHBB is a potential prognostic biomarker for GC and may drive the abnormal activity of critical cancer-associated pathways, potentially contributing to immune cell infiltration to promote GC development.

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Project description:ObjectiveGliomas are the most common and life-threatening intracranial tumors. Immune infiltration of the tumor microenvironment significantly affects tumor prognosis in glioma. Recently, PLEKHA4 was reported to be upregulated in melanoma and closely associated with tumor genesis and development, but its role in glioma is poorly understood. Our aim was to investigate the expression, functional role, and prognostic value of PLEKHA4 in glioma.MethodsThe expression levels of PLEKHA4 in 33 types of cancer in the TCGA (The Cancer Genome Atlas) database were collected via the UCSC Xena browser. The clinical samples of glioma patients were downloaded from the TCGA database. Immunohistochemistry was used to verify PLEKHA4 expression in tumor tissues. We assessed the influence of PLEKHA4 on survival of glioma patients by survival module and GEPIA. Then, we downloaded datasets of glioma from TCGA and investigated the correlations between the clinical characteristics and PLEKHA4 expression using logistic regression. Moreover, we used TIMER to explore the collection of PLEKHA4 expression and immune infiltration level in glioma and to analyze cumulative survival in glioma. Gene Set Enrichment Analysis (GSEA) was performed using the TCGA dataset.ResultsPLEKHA4 transcript levels were significantly upregulated in multiple cancer types, including gliomas. Moreover, immunohistochemical analysis verified that PLEKHA4 was overexpressed in gliomas compare to the corresponding normal tissues. Univariable survival and multivariate cox analysis show that increased PLEKHA4 expression significantly correlated with age, tumor grade, IDH mutation status, and 1p/19q codel status, and higher PLEKHA4 had shorter OS, DSS, and PFI. Specifically, PLEKHA4 expression level had significant positive correlations with infiltrating levels of B cell, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and DCs in glioma, and upregulation of PLEKHA4 expression was significantly related to immune cell biomarkers and immune checkpoint expression in glioma. In addition, several GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) items associated with immune response, JAK STAT signal pathway, and cell cycle were significantly enriched in the high PLEKHA4 expression phenotype pathway.ConclusionsOur findings proposed that PLEKHA4 was an independent prognostic biomarker and correlated with immune infiltrates in glioma, and targeting PLEKHA4 might improve immunotherapy in glioma. Of course, these findings also need basic experiments and further clinical trials to confirm in the future.

Project description:Colon adenocarcinoma (COAD) is one of the most serious cancers. It is important to accurately predict prognosis and provide individualized treatment. Evidence suggests that clinicopathological features and immune status of the body are related to the occurrence and development of cancer. Expression of long non-coding RNA (LncRNA) ALMS1 intronic transcript 1 (ALMS1-IT1) is observed in some cancer types, and we believe that it may have the potential to serve as a marker of COAD. Therefore, we used the data obtained from the cancer genome atlas (TCGA) database to prove the relationship between ALMS1-IT1 and COAD. Wilcoxon rank sum test, Chi-square test, Fisher exact test and logistic regression were used to evaluate relationships between clinical-pathologic features and ALMS1-IT1 expression. Receiver operating characteristic curves were used to describe binary classifier value of ALMS1-IT1 using area under curve score. Kaplan-Meier method and Cox regression analysis were used to evaluate factors contributing to prognosis. Gene oncology (GO) and (Kyoto Encyclopedia of Genes and Genomes) KEGG enrichment analysis were used to predict the function of differentially expressed genes associated with ALMS1-IT1. Gene set enrichment analysis (GSEA) was used to predict canonical pathways associated with ALMS1-IT1.Immune infiltration analysis was performed to identify the significantly involved functions of ALMS1-IT1. Starbase database was used to predict miRNAs and RNA binding proteins (RBPs) that may interact with ALMS1-IT1. Increased ALMS1-IT1 expression in COAD was associated with N stage (P < .001), M stage (P = .003), Pathologic stage (P = .002), and Primary therapy outcome (P = .009). Receiver operating characteristic curve suggested the significant diagnostic and prognostic ability of ALMS1-IT1 (area under curve = 0.857). High ALMS1-IT1 expression predicted a poorer overall-survival (P = .005) and poorer progression-free interval (PFI) (P = .012), and ALMS1-IT1 expression was independently correlated with PFI in COAD patients (hazard ratio (HR) :1.468; 95% CI: 1.029-2.093; P =.034) (HR: 1.468; 95% CI: 1.029-2.093; P = .034). GO, KEGG, GSEA, and immune infiltration analysis showed that ALMS1-IT1 expression was correlated with regulating the function of DNA and some types of immune infiltrating cells. ALMS1-IT1 expression was significantly correlated with poor survival and immune infiltrations in COAD, and it may be a promising prognostic biomarker in COAD.

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CHI3L2 Is a Novel Prognostic Biomarker and Correlated With Immune Infiltrates in Gliomas.

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