Guanylate binding protein 4 shapes an inflamed tumor microenvironment and identifies immuno-hot tumors.

PURPOSE: Guanylate binding protein 4 (GBP4) is induced by interferons and various cytokines and has been recognized as functionally relevant in numerous types of human cancers. While the role of GBP4 in cancer has been preliminarily summarized, its correlation with antitumor immunity remains unclear and requires further research. METHODS: First, a comprehensive pan-cancer analysis was conducted, focusing on GBP4's expression patterns and immunological functions. Subsequently, we explored the correlations between GBP4 and immunological features within the tumor microenvironment (TME) in non-small cell lung cancer (NSCLC) patients. Additionally, we examined the relationships between GBP4 and emerging immunobiomarkers, such as N6-methyladenosine (m6A) genes. Moreover, we assessed the utility of GBP4 in predicting the clinical characteristics and treatment responses of patients with NSCLC. RESULTS: Pan-cancer analysis revealed that GBP4 plays a positive role in most cancer types via the majority of immunomodulators. Furthermore, GBP4 demonstrated positive associations with immunomodulatory factors, tumor-infiltrating immune cells (TIICs) and inhibitory immune checkpoints. Remarkably, the expression of GBP4 was found to be a predictor of significantly enhanced responsiveness to anti-EGFR therapy and immunotherapy. CONCLUSIONS: GBP4 expression profiles offer a promising avenue for identifying highly immunogenic tumors across a wide spectrum of cancers. GBP4 holds potential as a robust pan-cancer biomarker for assessing the immunological characteristics of tumors, with particular relevance to its ability to predict therapeutic responses, notably in the context of anti-EGFR therapy and immunotherapy.

Comprehensive Analysis Reveals the Potential Roles of CDKN3 in Pancancer and Verification in Endometrial Cancer.

Background: Cyclin-dependent kinase inhibitor 3 (CDKN3) has been studied in many cancers. However, the comprehensive and systematic pancancer analysis of CDKN3 genes is still lacking. Methods: Data were downloaded from online databases. R was used for analysis of the differential expression and gene alteration of CDKN3 and of the associations between CDKN3 expression and survival, signaling pathways, and drug sensitivity. Clinical samples and in vitro experiments were selected for verification. Results: CDKN3 expression was higher in most types of cancers, and this phenotype was significantly correlated with poor survival. CDKN3 showed gene alterations and copy number alterations in many cancers and associated with some immune-related pathways and factors. Drug sensitivity analysis elucidated that CDKN3 could be a useful marker for therapy selection. Clinical samples elucidated CDKN3 expressed high in endometrial cancer tissue. In vitro studies showed that CDKN3 induced pro-tumor effect in immune environment and facilitated endometrial cancer cell proliferation and G1/S phase transition. Conclusion: CDKN3 has been shown to be highly expressed in most types of cancers and promoted cancer cell progression. CDKN3 may serve as a novel marker in clinical diagnosis, treatment, and prognosis prediction in future.

Identification of the function of FOSB in cholangiocarcinoma using bioinformatics analysis.

Background: Exploring the potential mechanism of cholangiocarcinoma (CCA) metabolic reprogramming is significant for guiding clinical treatment. However, related research and exploration are still lacking. Therefore, we aimed to identify a reliable metabolism-related gene or biomarker of CCA using bioinformatics analysis. Methods: The GSE26566, GSE45001, and GSE132305 datasets were obtained from the Gene Expression Omnibus (GEO) database. Differently expressed genes (DEGs) between CCA tissues and adjacent tissues were screened out. The key gene was identified through enrichment and functional analysis, and its immune and clinical correlation was investigated utilizing the Tumor Immune Evaluation Resource (TIMER2.0), the Tumor-Immune System Interactions Database (TISIDB), the Gene Expression Profiling Interactive Analysis (GEPIA2), and the Kaplan-Meier Plotter. Finally, immunohistochemistry (IHC) was performed to validate the results. Results: By analysis, the expression of FBJ murine osteosarcoma viral oncogene homolog B (FOSB) was significantly downregulated in CCA tissues when compared with adjacent tissues. Moreover, the expression levels of FOSB positively correlated with tumor-infiltrating immune cells in most tumors, and patients with high FOSB expression tended to have a better prognosis. The FOSB and SIRT3/HIF1A axes have similar expression trends and metabolic functions in CCA cells, and the correlation between of them was preliminarily explored by IHC experiments. Conclusions: The expression levels of FOSB are closely related to the prognosis of CCA patients, which may be a predictive indicator for prognosis and immunotherapy.

A functional reference map of the RNF8 interactome in cancer.

BACKGROUND: RNF8 is an E3 ligase identified as a critical DNA damage-responsive protein. Recently, multiple reports have shown that RNF8 could be used as an important therapeutic target for cancer chemo/radiotherapy. However, the understanding of RNF8 remains limited due to the lack of its interactome reference map and comprehensive analysis of RNF8 in diverse cancers, which underscores the need to map the interactome of RNF8 via high-throughput methods. RESULTS: A two-way identification method based on LC-MS was designed for the identification of the RNF8 interactome with high-specificity. By in silico analysis and in vitro validation, we identified a new reference map of the RNF8 interactome network containing many new targets, such as YBX1, DNMT1, and HDCA1, new biological functions and the gene-disease associations of RNF8. Our results revealed a close relationship between RNF8 and neurodegenerative diseases or tumor-infiltrating immune cells using bulk RNA-seq and scRNA-seq datasets. As a proof of concept of our interactome map, we validated the direct binding between RNF8 and YBX1 and showed that RNF8 catalyzed the ubiquitination of YBX1. These results demonstrated that RNF8 might be a crucial regulator of YBX1. CONCLUSIONS: Our work provides a unique framework for researchers and clinicians who seek to better explore or understand RNF8-regulated biological functions in cancers. This study will hopefully facilitate the rational design and further development of anti-RNF8 therapy in cancers.

OAS3 is a Co-Immune Biomarker Associated With Tumour Microenvironment, Disease Staging, Prognosis, and Treatment Response in Multiple Cancer Types.

2',5'-oligoadenylate synthase (OAS) is a class of enzymes induced by interferons and mainly encoded by the OAS1, OAS2, and OAS3 genes, which activate the potential RNA enzymes to degrade viral mRNA, inhibit viral protein synthesis and promote apoptosis in virus-infected cells. OAS3 is associated with breast cancer prognosis. However, the expression and prognosis of OAS3 and tumour-infiltrating lymphocytes in pan-cancer remain unknown. In the present study, we have systematically investigated and confirmed the role of OAS3 in tumour immune infiltration, immune escape, tumour progression, response to treatment, and prognosis of different cancer types using various bioinformatics methods. The findings suggest that OAS3 is aberrantly expressed in almost all TCGA cancer types and subtypes and is associated with tumour staging, metastasis, and prognostic deterioration in different tumours. In addition, OAS3 expression is associated with the prognosis and chemotherapeutic outcomes of various cancers. In terms of immune-infiltrating levels, OAS3 expression is positively associated with the infiltration of immunosuppressive cells. These findings suggest that OAS3 is correlated with prognosis and immune-infiltrating levels.

Chromobox Homolog 8 (CBX8) in Human Tumor Carcinogenesis and Prognosis: A Pancancer Analysis Using Multiple Databases.

Some emerging studies have suggested that chromobox homolog 8 (CBX8) may play a critical role in carcinogenesis and prognosis in human cancer. Based on The Cancer Genome Atlas (TCGA)'s available data and the Gene Expression Omnibus (GEO) database, we conducted a systematic analysis of the carcinogenic effects of the CBX8 gene. We used TIMER2, GEPIA2, UALCAN, cBioPortal, Kaplan-Meier plotter, OncoLnc, STRING, HPA, and Oncomine data analysis websites and R data analysis software to analyze available data. The results show that the level of expression of CBX8 was significantly different among 27 different types of tumors and adjacent normal tissues. Moreover, we found that CBX8 expression had a close relationship with prognosis in some kinds of cancers. The phosphorylation level of some protein sites (such as S256) was significantly increased in tumors. CD8 + T-cell, B-cell and cancer-associated fibroblast infiltration levels were associated with CBX8 expression. The results of enrichment analysis indicated that the main biological activities of CBX8 are connected to gene transcription and repair of DNA damage. In conclusion, the level of expression of CBX8 was closely related to carcinogenesis and prognosis of some kinds of tumors, which needs further experimental verification.

Pan-Cancer Molecular Characterization of m6A Regulators and Immunogenomic Perspective on the Tumor Microenvironment.

PURPOSE: N6-methyladenosine (m6A) methylation plays a critical role in diverse biological processes. However, knowledge regarding the constitution of m6A on tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) across cancer types is still lacking. We performed comprehensive immuno-genomic analyses to reveal molecular characterization of the m6A regulators and immune-related genes (IRGs) across TME and TIL heterogeneity. METHODS: We comprehensively analyzed the properties of m6A regulators in genomic profiles from The Cancer Genome Atlas (TCGA) according to expression perturbations of crucial IRGs, CD274, CD8A, GZMA, and PRF1. The four IRGs were proved to be reliable biomarkers of TILs and TME via CIBERSORT and ESTIMATE analyses, and their co-expression relationship was certified by TIMER analysis. Based on their median values, the samples from the pan-cancer tissues (N = 11,057) were classified into eight TME types. The RNA expression levels of 13 m6A regulators were compared across TME subtypes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was also used to classify TME clusters, expression variants of IRGs and m6A regulators were verified among TME clusters. Meanwhile, the correlation between m6A regulators and tumor mutational burden (TMB) were tested. Finally, the impacts of IRGs and TME clusters in clinical characteristics and outcomes were revealed. RESULTS: CD274, CD8A, GZMA, and PRF1 showed similar TILs' characteristics, of which the level of T cells CD8 and T cells CD4 memory activated are consistent with the expression levels of the four IRGs and higher immune infiltration. Besides, CD274, CD8A, GZMA, and PRF1 were positively correlated with the stromal score or immune score in almost all 33 tumor types. All of four IRGs showed impact between tumor pathological stages or clinical outcomes. Among TME type I to type IV, m6A regulators' expression drift changed from high-level to low-level in ESCA, BLCA, HNSC, CESC, BRCA, and GBM. However among TME type V to type VIII, m6A regulators drew a shift from low-level to high-level expression in CESC, BLCA, ESCA, KIRP, HNSC, BRCA, KIRC, COAD, LAML, GBM, and KICH. In ssGSEA analyses, IRGs' expression levels were elevated with the immune infiltration degree and m6A regulators' expression level varied among three TIL subgroups. With different TMB levels, expression differences of m6A regulators were observed in BLCA, BRCA, COAD, LGG, LUAD, LUSC, STAD, THCA, and UCEC. CONCLUSION: We identified four crucial IRGs affecting TILs, TME characteristics and clinical parameters. Expression variants of m6A regulators among the subgroups of TME types and ssGSEA clusters suggested that m6A regulators may be essential factors for phenotypic modifications of IRGs and thus affecting TME characteristics across multiple tumor types.

RNA editing in cancer: Mechanistic, prognostic, and therapeutic implications.

We have recently provided a comprehensive analysis of A-to-I RNA editing events in various cancer types, revealing many clinically relevant RNA editing sites and demonstrating that RNA editing can selectively affect cancer drug sensitivity. Our results unveil mechanistic, prognostic, and therapeutic implications for RNA editing in cancer.