Propofol Suppresses Glioma Tumorigenesis by Regulating circ_0047688/miR-516b-5p/IFI30 Axis.

Propofol has recently attracted increasing attention for its anti-tumor property in cancers, including glioma. Circular RNAs (circRNAs) can act as key regulators in various cancers. However, the relationship between propofol and circ_0047688 in glioma is still unclear. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and colony formation assays. Cell migration and invasion were determined using transwell assay. Cell apoptosis was detected by flow cytometry. Protein levels and RNA levels were detected by western blot assay and real-time quantitative polymerase chain reaction (RT­qPCR), respectively. The intermolecular interaction was predicted by bioinformatics analysis and verified by dual-luciferase reporter assay. A mouse xenograft model was established for in vivo experiments. Propofol inhibited cell proliferation, migration, and invasion and accelerated apoptosis in glioma cells. Circ_0047688 was upregulated in glioma tissues and cells, and propofol downregulated circ_0047688 in a dose-dependent manner. Circ_0047688 knockdown inhibited glioma cell progression and its overexpression abated the anti-tumor role of propofol in glioma cells. Moreover, miR-516b-5p was a direct target of circ_0047688, and circ_0047688 promoted glioma cell progression by sponging miR-516b-5p. In addition, IFI30 was a direct target of miR-516b-5p, and miR-516b-5p inhibited glioma cell malignant behaviors by targeting IFI30 in propofol-treated cells. Furthermore, circ_0047688 overexpression could weaken the anti-tumor role of propofol in vivo. Propofol inhibited glioma progression via modulating circ_0047688/miR-516b-5p/IFI30 axis, providing a potential therapeutic strategy for treatment of glioma.

IFI30 expression predicts patient prognosis in breast cancer and dictates breast cancer cells proliferation via regulating autophagy.

Introduction: Incidence and mortality rates of breast cancer are increasing in women worldwide. Immunotherapy is a relatively popular treatment modality for all malignant tumors including breast cancer in recent years. Interferon γ-inducible protein 30 (IFI30) could catalyze the reduction of disulfide bonds and enhance major histocompatibility complex (MHC) class II-restricted antigen processing. Recent studies showed that IFI30 played an important role in the immune response of malignant tumors. Methods: The Cancer Genome Atlas (TCGA) database and clinical proteomic tumor Analysis consortium (CPTAC) database were applied to predict the role of IFI30 in breast cancer and the relationship between IFI30 and prognosis of breast cancer patients. Then we detected the expression of IFI30 in clinical samples of breast cancer patients, and analyzed the relationship between IFI30 and the prognosis of breast cancer patients. We used lentivirus infection method to construct a stable IFI30 knockdown cell line, and detected the effect of IFI30 in breast cancer cells. Nude mice tumor bearing experiment was performed to investigate the effect of IFI30 on breast cancer cells in vivo. Western blot was used to verify the regulation of autophagy related protein LC3 and p62 by IFI30. Results: We found that IFI30 was highly expressed in breast cancer tissues and was associated with poor outcome of patients. The knockdown of IFI30 could inhibit the proliferation, migration and invasion of breast cancer cells and significantly inhibit tumor growth in vivo. Increased accumulation of LC3-II and p62 suggested impaired autophagy in IFI30 knockdown cells. Discussion: As a result, we suggested that IFI30 might play a key role in the initiation and progression of human breast cancer and might be a new therapeutic target in breast cancer.

IFI30 expression is an independent unfavourable prognostic factor in glioma.

Gamma-interferon-inducible lysosomal thiol reductase, the only known lysosomal thiol reductase, is encoded by gene IFI30 and expressed constitutively in antigen-presenting cells. Our comprehensive study on IFI30 in gliomas found its expression to be high in glioblastomas and in gliomas with a mesenchymal subtype or wild-type isocitrate dehydrogenase, all of which indicated the malignancy and poor outcomes of gliomas. Kaplan-Meier survival analysis ascertained that high IFI30 expression conferred poor outcomes. The IFI30 expression levels also showed high efficiency in predicting 1-, 3- and 5-year overall survival. Univariable and multivariable Cox regression analyses were performed to define IFI30 as an independent prognostic marker. Biological process analysis suggested that IFI30 was involved in immune responses. ESTIMATE and CIBERSORT were applied to evaluate immune cell infiltration, with results indicating that samples with higher IFI30 expression had higher infiltration of immune cells, including regulatory T cells and M0 macrophages. Correlation analysis showed that IFI30 was significantly positively correlated with immune checkpoints that suppress effective antitumour immune responses. Immunohistochemical staining was also performed to confirm the association between IFI30 expression and the immune phenotype. The suggested correlation between high IFI30 expression and an immunosuppressive phenotype contributes to our knowledge about the glioma microenvironment and might provide clues for the development of novel therapeutic targets.

IFI30 as a key regulator of PDL1 immunotherapy prognosis in breast cancer.

BACKGROUND: IFI30 is a lysosomal thiol reductase involved in antigen presentation and immune regulation in various cancers, including breast cancer. Despite its known involvement, the precise mechanism, function, and relationship with the PD-L1 axis and immune response remain unclear. METHODS: We conducted an extensive investigation into IFI30 mRNA expression in breast cancer utilizing data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Furthermore, we characterized IFI30 mRNA expression across various cell types using publicly available single-cell RNA sequencing datasets, and assessed protein expression through immunohistochemistry using an in-house breast cancer tissue microarray. Functional experiments were performed to elucidate the effects of IFI30 overexpression on PD-L1 expression and inhibitory efficacy in both macrophages and breast tumor cells. RESULTS: Our study unveiled a marked upregulation of IFI30 expression in breast cancer tissues compared to their normal counterparts, with notable associations identified with tumor stage and prognosis. Additionally, IFI30 expression demonstrated significant correlations with various immune-related signaling pathways, encompassing peptide antigen binding, cytokine binding, and MHC class II presentation. Notably, breast cancer samples exhibiting high IFI30 expression in tumor cells displayed high PD-L1 expression on corresponding cells, alongside a diminished ratio of CD8 + T cell infiltration within the tumor microenvironment. Furthermore, ectopic knockdown of IFI30 in both tumor cells and macrophages resulted in a reduction of PD-L1 expression, while conversely, overexpression of IFI30 led to an increase in PD-L1 expression. CONCLUSIONS: This study offers new insights into the involvement of IFI30 in breast cancer, elucidating its interplay with the PD-L1 axis and immune response dynamics. Our findings suggest that modulation of the IFI30-PD-L1 axis could serve as a promising strategy for regulating T cells infiltration in breast cancer thus treating breast cancer.

A Transcription Factor ZNF384, Regulated by LINC00265, Activates the Expression of IFI30 to Stimulate Malignant Progression in Glioma.

Glioma remains one of the most challenging primary brain malignancies to treat. Long noncoding RNAs (lncRNAs) and mRNAs (mRNAs) are implicated in regulating the malignant phenotypes of cancers including glioma. This study aimed to elucidate the functions and mechanisms of lncRNA LINC00265 and mRNA IFI30 in the pathogenesis of glioma. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis revealed the upregulated expression of LINC00265 and IFI30 in glioma cells compared to normal human astrocytes. Western blot (WB) quantified the associated proteins. Glioma stemness and epithelial-to-mesenchymal transition (EMT) were assessed by aldehyde dehydrogenase 1 (ALDH1) activity, sphere formation, and WB. Mechanistic and rescue assays evaluated the LINC00265/miR-let-7d-5p/IFI30/ZNF384/IGF2BP2 axis. The results demonstrated that LINC00265 and IFI30 were highly expressed in glioma cells, promoting stemness and EMT. ZNF384 was identified as a transcription factor that upregulates IFI30. Moreover, LINC00265 elevated ZNF384 by sponging miR-let-7d-5p and recruiting IGF2BP2. In conclusion, LINC00265 and IFI30 act as oncogenes in glioma by driving stemness and EMT, underscoring their potential as therapeutic targets.

Ifi30 Is Required for Sprouting Angiogenesis During Caudal Vein Plexus Formation in Zebrafish.

Interferon-gamma-inducible protein 30 (IFI30) is a critical enzyme that mainly exists in immune cells and functions in reducing protein disulfide bonds in endocytosis-mediated protein degradation. Regardless of this, it is also found to be expressed in vascular system. However, the functions of IFI30 in vascular development remains unknown. Vascular network formation is a tightly controlled process coordinating a series of cell behaviors, including endothelial cell (EC) sprouting, proliferation, and anastomosis. In this work, we analyzed the function of zebrafish Ifi30, orthologous to the human IFI30, in vascular development during embryogenesis. The ifi30 gene was found to be highly expressed in the caudal vein plexus (CVP) region of zebrafish embryos. Morpholino-mediated Ifi30 knockdown in zebrafish resulted in incomplete CVP formation with reduced loop numbers, area, and width. Further analyses implied that Ifi30 deficiency impaired cell behaviors of both ECs and macrophages, including cell proliferation and migration. Here, we demonstrate a novel role of IFI30, which was originally identified as a lysosomal thiol reductase involved in immune responses, in CVP development during embryogenesis. Our results suggest that Ifi30 is required for sprouting angiogenesis during CVP formation, which may offer an insight into the function of human IFI30 in angiogenesis under physiological or pathological conditions.

Identification of CD8+ T cell infiltration-related genes and their prognostic values in cervical cancer.

Cervical cancer is a female-specific cancer with relatively high morbidity and mortality. As known to all, immune cell infiltrations in the cancer microenvironment are closely related to the cancer diagnosis and prognosis. Here we revealed that the CD8+ T cell infiltration was significantly upregulated in cervical cancer versus normal cervix uteri samples. Through univariate and multivariate cox analyses, we discovered that the CD8+ T cell infiltration was the only independent beneficial factor for the prognosis of cervical cancer. To explore the genes associated with the CD8+ T cell infiltration in cervical cancer, we performed the WGCNA analysis on the differentially expressed genes (DEGs) of cervical cancer versus normal cervix uteri tissues. As a result, 231 DEGs were found to be associated with CD8+ T cell infiltration in cervical cancer. Subsequently, with the Cytoscape analysis, we identified 105 hub genes out of the 231 DEGs. To further explore the genes that might be responsible for the prognosis of cervical cancer, we performed a univariate cox analysis followed by a LASSO assay on the 105 hub genes and located four genes (IGSF6, TLR10, FCRL3, and IFI30) finally. The four genes could be applied to the prediction of the prognosis of cervical cancer, and relatively higher expression of these four genes predicted a better prognosis. These findings contributed to our understanding of the prognostic values of CD8+ T cell infiltration and its associated genes in cervical cancer and thus might benefit future immune-related therapies.

IFI30 as a prognostic biomarker and correlation with immune infiltrates in glioma.

BACKGROUND: Increased evidence indicates that the tumour microenvironment (TME) plays an essential role in the development, treatment and prognosis of glioma. High expression of interferon-gamma-inducible protein 30 (IFI30) is associated with the malignant phenotype, but the effect of IFI30 on the tumour immune microenvironment and its potential role in the carcinogenesis of glioma remain unknown. METHODS: The RNA sequencing (RNA-seq) data of 33 types of human cancer were obtained from The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC). R software was used to perform analyses, such as the expression of IFI30 in pan-cancer, evaluation of IFI30 as a prognostic biomarker in glioma, the relationship between IFI30 expression and clinical characteristics, and immune checkpoint. TIMER was used to analyse the correlation of IFI30 expression level with immune cell infiltration, and also to conduct survival analysis for immune cells and IFI30 in low grade glioma (LGG). DAVID was used for Gene Ontology (GO) functional annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) for pathway analysis of the genes similar to IFI30 in glioma. The differentially expressed genes (DEGs) between the high- and low-IFI30 expression groups were determined by DESeq2. Gene set enrichment analysis (GSEA) was then conducted to identify IFI30-related functional significance based on the hallmark gene set. RESULTS: Dysregulated expression of IFI30 was associated with human cancers. High IFI30 expression was associated with poor overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI). Univariate and multivariate analyses identified IFI30 as an independent predictor for glioma. Meanwhile, IFI30 overexpression significantly correlated with high-grade tumours, poor OS, and immune infiltration. In addition, IFI30-associated genes significantly enriched the hallmark tumour progression-related clusters and cancer pathways. CONCLUSIONS: IFI30 is a prognostic biomarker correlated with immune infiltrates and acts as an oncogene in glioma.

IFI30 Is a Novel Immune-Related Target with Predicting Value of Prognosis and Treatment Response in Glioblastoma.

PURPOSE: As a crucial part of anti-tumor immunotherapy, interferon-α/ß (IFN-α/ß) treatment has been broadly applied to clinical trials of glioma. However, less is known about implement of interferon-γ (IFN-γ) in glioma. Further investigating the valuable hub molecular of IFN-γ family might provide us a novel guidance for glioma therapy. METHODS: This study carried out an analysis on glioma patients from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) cohorts. The analyses were performed by GraphPad Prism 8 and R language. All the validated experiments were performed three times independently. RESULTS: We identified IFI30 as the most stable independent prognostic gene among 20 classical IFN-γ stimulated genes (ISGs) in glioma patients. Furthermore, we found that IFI30 highly expressed in malignant subtypes of glioma and associated with chemotherapy response. We also found IFI30 could activate IL6-STAT6 signal pathway to decline the glioma cells' chemotherapy sensitivity by performing experiments. Gene ontology (GO) analysis showed IFI30 associated with enhanced leucocyte mediated immune and inflammatory response. Microenvironment analysis referred that high IFI30 expression accompanied with more infiltration of M2 type macrophages. CONCLUSION: IFI30 is involved in the malignant progression and chemotherapy response of glioblastoma, which can be a potential target for treatment in glioblastoma patients.

The association of genetic variants IL2RA rs2104286, IFI30 rs11554159 and IKZF3 rs12946510 with multiple sclerosis onset and severity in patients from Serbia.

An algorithm Probabilistic Identification of Causal SNPs, identified 434 causal variants for multiple sclerosis (MS) including IL2RA rs2104286, IFI30 rs11554159 and IKZF3 rs12946510. Analysis of individual and combined effects of these variants in the Serbian population identified that Il2RA rs2104286 G allele carriers had a lower risk for developing MS (gender adjusted OR = 0.63, p = .003). With regard to the IFI30 rs11554159 recessive genetic model, among HLA-DRB1*15:01 positive patients, the AA homozygote had a significantly higher MSSS compared to the G allele carriers (p = .003). This study confirms role of IL2RA rs2104286 in MS and suggest the role of IFI30 rs11554159 in disease severity, which needs validation.

Microglia express gamma-interferon-inducible lysosomal thiol reductase in the brains of Alzheimer's disease and Nasu-Hakola disease.

Gamma-interferon-inducible lysosomal thiol reductase (GILT), expressed in antigen-presenting cells (APCs), facilitates the reduction of disulfide bonds of endocytosed proteins in the endocytic pathway and they are further processed for presentation of immunogenic peptides loaded on major histocompatibility complex (MHC) class II. Although the constitutive and IFNγ-inducible expression of GILT was observed in various APCs, such as dendritic cells, monocytes/macrophages, and B cells, GILT-expressing cell types remain unknown in the human central nervous system (CNS). Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by sclerosing leukoencephalopathy and multifocal bone cysts, caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2, both of which are expressed on microglia. A rare heterozygous variant of the TREM2 gene encoding p.Arg47His causes a 3-fold increase in the risk for late-onset Alzheimer's disease (LOAD), suggesting that both NHD and AD are induced by dysfunction of the microglial TREM2 signaling pathway in the brains. We studied by immunohistochemistry GILT expression in NHD and AD brains. GILT was expressed on amoeboid microglia with the highest levels of expression in AD brains, compared with those in non-neurological control (NC) brains and in NHD brains. In AD brains, the clusters of amoeboid microglia surrounding amyloid-beta (Aꞵ) deposition strongly expressed GILT. Furthermore, a human microglial cell line expressed GILT in response to IFNγ. These results indicate that microglia, expressing constitutively high levels of GILT, act as a principal cell type of APCs in AD brains, in contrast to baseline levels of GILT expression in NHD brains.

Porcine IFI30 inhibits PRRSV proliferation and host cell apoptosis in vitro.

Interferon-gamma-inducible protein 30 (IFI30) is an IFN-γ-inducible protein that is involved in MHC class II-restricted antigen processing and MHC class I-restricted cross-presentation pathways of adaptive immunity. The present study aimed to investigate the effects of porcine IFI30 expression on PRRSV proliferation in host cells. MARC-145 cells and pig Sertoli (ST) cells were infected with PRRSV after transfection with porcine IFI30 expression vectors and an empty vector. PRRSV copy numbers were analyzed by absolute real-time quantitative PCR, and the results showed that porcine IFI30 expression could significantly inhibit PRRSV transcription. Western blot analysis also determined that IFI30 expression could reduce the production of PRRSV M protein. Flow cytometric analysis indicated that the apoptosis of MARC-145 cells, which are non-porcine but highly permissive to PRRSV cells, was significantly decreased in the IFI30 expression group. In porcine ST cells, apoptosis was significantly increased in IFI30 knockdown cells but not in IFI30-overexpressing cells (**p < 0.01). In conclusion, porcine IFI30 expression may inhibit PRRSV proliferation and host cell apoptosis in vitro.

Diverse cellular and organismal functions of the lysosomal thiol reductase GILT.

Gamma-interferon-inducible lysosomal thiol reductase (GILT) is the only enzyme known to catalyze disulfide bond reduction in the endocytic pathway. GILT facilitates the presentation of a subset of epitopes from disulfide bond-containing antigens. Enhanced presentation of MHC class II-restricted epitopes alters central tolerance and modulates CD4+ T cell-mediated autoimmunity. Improved cross-presentation of viral epitopes results in improved cross-priming of viral-specific CD8+ T cells. GILT regulates the cellular redox state. In GILT-/- cells, there is a shift from the reduced to the oxidized form of glutathione, resulting in mitochondrial autophagy, decreased superoxide dismutase 2, and elevated superoxide levels. GILT expression diminishes cellular activation, including decreased phosphorylated ERK1/2, and decreases cellular proliferation. GILT enhances the activity of bacterial hemolysins, such as listeriolysin O, and increases bacterial replication and infection. GILT expression in cancer cells is associated with improved patient survival. These diverse roles of GILT are discussed.