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Small extracellular vesicles (sEVs) are cell-derived, nanometer-sized particles enclosed by a lipid bilayer. All kinds of biological molecules, including proteins, DNA fragments, RNA, lipids, and metabolites, can be selectively loaded into sEVs and transmitted to recipient cells that are near and distant. Growing shreds of evidence show the significant biological function and the clinical significance of sEVs in cancers. Numerous recent studies have validated that sEVs play an important role in tumor progression and can be utilized to diagnose, stage, grading, and monitor early tumors. In addition, sEVs have also served as drug delivery nanocarriers and cancer vaccines. Although it is still infancy, the field of basic and translational research based on sEVs has grown rapidly. In this review, we summarize the latest research on sEVs in gliomas, including their role in the malignant biological function of gliomas, and the potential of sEVs in non-invasive diagnostic and therapeutic approaches, i.e., as nanocarriers for drug or gene delivery and cancer vaccines.
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BACKGROUND: Super-enhancers (SEs), driving high-level expression of genes with tumor-promoting functions, have been investigated recently. However, the roles of super-enhancer-associated lncRNAs (SE-lncRNAs) in tumors remain undetermined, especially in gliomas. We here established a SE-lncRNAs expression-based prognostic signature to choose the effective treatment of glioma and identify a novel therapeutic target. METHODS: Combined analysis of RNA sequencing (RNA-seq) data and ChIP sequencing (ChIP-seq) data of glioma patient-derived glioma stem cells (GSCs) screened SE-lncRNAs. Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets served to construct and validate SE-lncRNA prognostic signature. The immune profiles and potential immuno- and chemotherapies response prediction value of the signature were also explored. Moreover, we verified the epigenetic activation mechanism of LINC00945 via the ChIP assay, and its effect on glioma was determined by performing the functional assay and a mouse xenograft model. RESULTS: 6 SE-lncRNAs were obtained and identified three subgroups of glioma patients with different prognostic and clinical features. A risk signature was further constructed and demonstrated to be an independent prognostic factor. The high-risk group exhibited an immunosuppressive microenvironment and was higher enrichment of M2 macrophage, regulatory T cells (Tregs), and Cancer-associated fibroblasts (CAFs). Patients in the high-risk group were better candidates for immunotherapy and chemotherapeutics. The SE of LINC00945 was further verified via ChIP assay. Mechanistically, BRD4 may mediate epigenetic activation of LINC00945. Additionally, overexpression of LINC00945 promoted glioma cell proliferation, EMT, migration, and invasion in vitro and xenograft tumor formation in vivo. CONCLUSION: Our study constructed the first prognostic SE-lncRNA signature with the ability to optimize the choice of patients receiving immuno- and chemotherapies and provided a potential therapeutic target for glioma.
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Glioma , RNA Longo não Codificante , Humanos , Animais , Camundongos , Prognóstico , RNA Longo não Codificante/genética , Proteínas Nucleares , Fatores de Transcrição , Glioma/genética , Modelos Animais de Doenças , Microambiente Tumoral/genética , Proteínas de Ciclo CelularRESUMO
Osteosarcoma (OS) is a malignant bone tumor that most commonly occurs in children and adolescents. OS patients have a poor prognosis, and 5-year survival rates have rarely improved significantly over the past few decades. OS prognosis may be related to the infiltration of tumor-associated macrophages (TAMs). However, the role of proangiogenic macrophages, a subtype of TAMs, in OS prognosis has not been reported. In this study, seven subtypes of TAMs were identified from single-cell RNA sequencing (scRNA-seq) data that we propose defining as proangiogenic TAMs (Angio-TAMs), interferon-primed TAMs (IFN-TAMs), inflammatory cytokine-enriched TAMs (Inflam-TAMs), immune regulatory TAMs (Reg-TAMs), lipid-associated TAMs (LA-TAMs), and resident-tissue macrophages like TAMs (RTM-TAMs) (containing two subcellular types). In the survival analysis of each macrophage subtype, it was found that patients with Angio-TAMs had the most significant difference in survival. Eight genes associated with Angio-TAMs were obtained by differential expression analysis, and these genes were built into a prognostic model using the LASSO algorithm. Clinical OS case samples were categorized into high-risk and low-risk subgroups using median risk scores. In comparison to the low-risk subgroup, the survival time of the high-risk subgroup was much shorter. Additional studies on immune cell infiltration and immune checkpoint molecule expression in the two risk subgroups were carried out. In immunotherapy response prediction, the Angio-TAM-associated gene risk signature was found to be negatively correlated with immune checkpoint responses. In addition, the associated enriched GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were mainly involved in the malignant progression of tumors. As suggested by these findings, the Angio-TAM gene risk signature may be an underlying prognostic biomarker and novel therapeutic target for OS patients.Kindly check and confirm whether the ESM file is correctly identifiedWe have checked this file and confirmed that it can be correctly identified.
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Osteosarcoma (OS) is a frequent primary malignant bone tumor, with a poor prognosis. Necroptosis is strongly correlated with OS and may be an influential target for treating OS. This study's objective was to establish a necroptosis-related gene (NRG) prognostic signature that could predict OS prognosis and guide OS treatment. First, we identified 20 NRGs associated with OS survival based on the TARGET database. We then derived a 7 NRG prognostic signature. Our findings revealed that the 7 NRG prognostic signature performed well in predicting the survival of OS patients. We next analyzed differences in immunological status and immune cell infiltration. In addition, we examined the relationship between chemo/immunotherapeutic response and the 7-NRG prognostic signature. In addition, to probe the mechanisms underlying the NRG prognostic signature, we performed functional enrichment assays including GO and KEGG. Finally, CHMP4C was selected for functional experiments. Silencing CHMP4C prevented OS cells from proliferating, migrating, and invading. This 7-NRG prognostic signature seems to be an excellent predictor that can provide a fresh direction for OS treatment.
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Gliomas are the most common and fatal brain tumors worldwide. Abnormal DNA promoter methylation is an important mechanism for gene loss of tumor suppressors. A long non-coding RNA colorectal adenocarcinoma hypermethylated (CAHM) has been reported to be nearly deleted in glioblastomas (GBMs). Nevertheless, the roles of CAHM in gliomas remain unknown up to now. In the present study, 969 glioma samples downloaded from the CGGA and Gravendeel databases were included. We found that CAHM expression was correlated with glioma grades, molecular subtype, IDH mutation status, and 1q/19p codel status. In glioma cells, CAHM is hypermethylated by DNA methyltransferase1 (DNMT1) and the loss of CAHM expression could be reversed by 5-Aza-2'-deoxycytidine (5-Aza), a specific inhibitor of DNA methyltransferases. Besides, the expression of CAHM was negatively associated with overall survival in both primary and recurrent gliomas. Moreover, the result of Gene Ontology (GO) analysis suggested that CAHM participated in negatively regulating cell development, nervous system development, neurogenesis, and integrin-mediated signaling pathway. Overexpression of CAHM inhibited glioma cell proliferation, clone formation, and invasion. Further exploring results showed that CAHM overexpression suppressed glioma migration and invasion through SPAK/MAPK pathway. Collectively, this study disclosed that CAHM might be a suppressor in gliomas.
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Adenocarcinoma , Neoplasias Encefálicas , Neoplasias Colorretais , Glioma , RNA Longo não Codificante , Adenocarcinoma/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , DNA , DNA (Citosina-5-)-Metiltransferase 1 , Metilação de DNA/genética , Metilases de Modificação do DNA , Decitabina , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Humanos , Integrinas/genética , Sistema de Sinalização das MAP Quinases , RNA Longo não Codificante/genéticaRESUMO
BACKGROUND: Glioma is the most common brain tumor in adults and is characterized by a short survival time and high resistance to chemotherapy. It is imperative to determine the prognosis and therapy-related targets for glioma. Endoplasmic reticulum stress (ERS), as an adaptive protective mechanism, indicates the unfolded protein response (UPR) to determine cell survival and affects chemotherapy sensitivity, which is related to the prognosis of glioma. METHODS: Our research used the TCGA database as the training group and the CGGA database as the testing group. Lasso regression and Cox analysis were performed to construct an ERS signature-based risk score model in glioma. Three methods (time-dependent receiver operating characteristic analysis and multivariate and univariate Cox regression analysis) were applied to assess the independent prognostic effect of texture parameters. Consensus clustering was used to classify the two clusters. In addition, functional and immune analyses were performed to assess the malignant process and immune microenvironment. Immunotherapy and anticancer drug response prediction were adopted to evaluate immune checkpoint and chemotherapy sensitivity. RESULTS: The results revealed that the 7-gene signature strongly predicts glioma prognosis. The two clusters have markedly distinct molecular and prognostic features. The validation group result revealed that the signature has exceptional repeatability and certainty. Functional analysis showed that the ERS-related gene signature was closely associated with the malignant process and prognosis of tumors. Immune analysis indicated that the ERS-related gene signature is strongly related to immune infiltration. Immunotherapy and anticancer drug response prediction indicated that the ERS-related gene signature is positively correlated with immune checkpoint and chemotherapy sensitivity. CONCLUSIONS: Collectively, the ERS-related risk model can provide a novel signature to predict glioma prognosis and treatment.
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Neoplasias Encefálicas , Glioma , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Estresse do Retículo Endoplasmático , Glioma/genética , Glioma/metabolismo , Glioma/terapia , Humanos , Prognóstico , Fatores de Risco , Microambiente Tumoral/genéticaRESUMO
Acute lung injury is an acute inflammatory disease with high morbidity rate and high mortality rate. However, there is still no effective clinical treatment to date. Our previous studies found that NLRC5 was significantly increased in acute liver injury model induced by LPS to reduce the secretion of IL-6 and TNF-α. Nevertheless, there is no report on the role of NLRC5 in regulating the development of acute lung injury. In this study we successfully established a model of acute lung injury induced by tracheal instillation of LPS in mice, and found NLRC5 expression was apparently elevated in mouse lung tissue and primary alveolar macrophages. NLRC5 overexpression negatively regulated secretion of inflammatory cytokines in murine alveolar macrophage cells through NF-κB and p38 MAPK pathway inhibition. There is a positively feedback between NLRC5 and NF-κB or p38 MAPK pathway. This study may provide some new ideas for clinical prevention of lung injury.
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Lesão Pulmonar Aguda/induzido quimicamente , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/toxicidade , NF-kappa B/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Lesão Pulmonar Aguda/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Inflamação/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Cancer-related deaths did not apparently decrease in the past decades despite aggressive treatments. It's reported that cancer will become the leading cause of death worldwide in the twenty-first century. Increasing evidence has revealed that lncRNAs will emerge as promising cancer biomarkers or therapeutic targets in cancer treatment. LncRNA-ATB, a long noncoding RNA activated by TGF-ß, was found to be abnormally expressed in certain cancers and participate in the development and progression of tumors. In addition, aberrant lncRNA-ATB expression was also associated with clinical characteristics of tumors. The purpose of this review is to summarize functions and underlying mechanisms of lncRNA-ATB in tumors, and discuss whether lncRNA-ATB can be a biomarker and therapeutic target in cancers.
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Neoplasias/genética , RNA Longo não Codificante/genética , Fator de Crescimento Transformador beta/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células/genética , Progressão da Doença , Humanos , RNA Longo não Codificante/metabolismo , Fator de Crescimento Transformador beta/genéticaRESUMO
Glioma is the most aggressive primary brain tumor. We have previously provided evidence that IFITM3 promoted glioma cells migration. However, the mechanism of how IFITM3 regulates glioma cells invasion and whether IFITM3 participates in TGF-ß-mediated glioma invasion are still unknown. In this paper, we proved that IFITM3 was notably up-regulated in glioma tissues. Knockdown of IFITM3 suppressed STAT3 phosphorylation in vitro, and a specific STAT3 inhibitor AG490 reversed IFITM3-induced invasion of glioma cells. Furthermore, IFITM3 expression was induced by TGF-ß in glioma and IFITM3 knockdown abolished TGF-ß-mediated glioma cells invasion. Collectively, the results indicate that IFITM3/STAT3 axis may promote TGF-ß-induced glioma cells invasion. This study provided some suggestions for the clinical treatment of the brain tumor.
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Glioma/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Fator de Transcrição STAT3/metabolismo , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glioma/genética , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fosforilação , Proteínas de Ligação a RNA/genética , Fator de Transcrição STAT3/genética , Ativação Transcricional/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Tirfostinas/farmacologiaRESUMO
Noncoding RNAs (ncRNAs) were initially thought to be transcriptional byproducts. However, recent advances of ncRNAs research have increased our understanding of the importance of ncRNA in gene regulation and disease pathogenesis. Consistent with these developments, liver fibrosis research is also experiencing rapid growth in the investigation of links between ncRNAs and the pathology of this disease. The initial focus was on studying the function and regulation mechanisms of microRNAs (miRNAs). However, recently, elucidation of the mechanisms of long noncoding RNAs (lncRNAs) and lncRNA-mediated liver fibrosis has just commenced. In this review, we emphasize on abnormal expression of lncRNAs in liver fibrosis. Furthermore, we also discuss that the interaction of lncRNAs with miRNAs is involved in the regulation of the expression of protein-coding genes in liver fibrosis. Recent advances in understanding dysregulated lncRNAs expression and the lncRNAs-miRNAs interaction in liver fibrosis will help for developing new therapeutic targets and biomarkers of liver fibrosis.
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Cirrose Hepática/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Biomarcadores/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Cirrose Hepática/patologiaRESUMO
Glioma constitutes the most aggressive primary intracranial malignancy in adults. We previously showed that long noncoding RNA activated by TGF-ß (lncRNA-ATB) promoted the glioma cells invasion. However, whether lncRNA-ATB is involved in TGF-ß-mediated invasion of glioma cells remains unknown. In this study, quantitative real-time polymerase chain reaction and western blot analysis were used for detecting the mRNA and protein expression of related genes, respectively. Transwell assay was performed to assess the impact of lncRNA-ATB on TGF-ß-induced glioma cells migration and invasion. Immunofluorescence staining was utilized to characterize related protein distribution. Results showed that TGF-ß upregulated lncRNA-ATB expression in glioma LN-18 and U251 cells. Overexpression of lncRNA-ATB activated nuclear factor-κB (NF-κB) pathway and promoted P65 translocation into the nucleus, thus facilitated glioma cells invasion stimulated by TGF-ß. Similarly, lncRNA-ATB markedly enhanced TGF-ß-mediated invasion of glioma cells through activation P38 mitogen-activated protein kinase (P38/MAPK) pathway. Moreover, both the NF-κB selected inhibitor pyrrolidinedithiocarbamate ammonium and P38/MAPK specific inhibitor SB203580 partly reversed lncRNA-ATB induced glioma cells invasion mediated by TGF-ß. Collectively, this study revealed that lncRNA-ATB promotes TGF-ß-induced glioma cell invasion through NF-κB and P38/MAPK pathway and established a detailed framework for understanding the way how lncRNA-ATB performs its function in TGF-ß-mediated glioma invasion.
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Neoplasias Encefálicas/patologia , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , RNA Longo não Codificante/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Glioma/genética , Glioma/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , NF-kappa B/metabolismo , Invasividade Neoplásica/genética , RNA Longo não Codificante/genéticaRESUMO
Long non-coding RNAs (lncRNAs) are increasingly recognized as major players in regulating various biological processes. LncRNA HOX transcript antisense RNA (Hotair) has been extensively studied in cancer. However, the role of Hotair in liver fibrosis remains unknown. Here we observed that Hotair expression was significantly increased in CCl4-induced mouse liver fibrosis models, human fibrotic livers and activated hepatic stellate cells (HSCs) by TGF-ß1 stimulation. Enforced expression of Hotair in LX-2 cells promoted cell proliferation and activation while inhibition of its expression had an opposite effect. Furthermore, we found that Hotair may act as an endogenous 'sponge' of miR-148b, which regulates expression of the DNMT1/MEG3/p53 pathways in HSCs. Intriguingly, Hotair enhanced polycomb repressive complex 2 (PRC2) occupancy and histone H3K27me3 repressive marks, specifically at the MEG3 promoter region. Finally, we found that Hotair forms an RNA/DNA hybrid and recruits PRC2 to MEG3 promoter. These data suggest that Hotair inhibition may represent a promising therapeutic option for suppressing liver fibrosis.
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Células Estreladas do Fígado/metabolismo , Cirrose Hepática/genética , RNA Longo não Codificante/genética , Regulação para Cima , Animais , Linhagem Celular , DNA (Citosina-5-)-Metiltransferase 1/genética , Epigênese Genética , Regulação da Expressão Gênica , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genéticaRESUMO
Gliomas are the most common primary malignancy in the brain, accounting for 50-60%. Despite all the efforts of cytoreductive surgery in combination with intense chemoradiotherapy, glioma remains an incurable disease. Recent studies have shown that long noncoding RNAs (lncRNAs) are involved in the pathology of gliomas. LncRNAs are involved in many cellular processes, such as angiogenesis, invasion, cell proliferation, and apoptosis. In this review we focus on the dysregulation of lncRNAs in gliomas. We also address that epigenetic modification such as DNA methylation and microRNAs interact with lncRNAs in gliomas. In addition, the interaction of lncRNAs with signaling pathways in gliomas is discussed systematically, with particular emphasis on the interaction of lncRNAs with EZH2. Such approaches provide valuable insights into the potential future applications of lncRNAs in the treatment of gliomas.
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Glioma/genética , Terapia de Alvo Molecular , Complexo Repressor Polycomb 2/genética , RNA Longo não Codificante/genética , Apoptose/genética , Proliferação de Células/genética , Metilação de DNA/genética , Proteína Potenciadora do Homólogo 2 de Zeste , Glioma/patologia , Humanos , Invasividade Neoplásica/genética , Neovascularização Patológica/genética , Complexo Repressor Polycomb 2/biossíntese , RNA Longo não Codificante/metabolismo , Transdução de SinaisRESUMO
Malignant brain tumors are thought to be originate from a small population of cells that display stem cell properties, including the capacity of self-renewal, multipotent differentiation, initiation of tumor tissues. Cancer stem cells (CSCs) have been identified in gliomas in which they are named as glioma stem cells (GSCs). GSCs, sharing some characteristics with normal neural stem cells (NSCs), contribute to the cellular origin for primary gliomas and the recurrence of malignant gliomas after current conventional therapy. Recently, increasing evidences have showed that miRNAs play a central role in GSCs. In this review we focus on the role of GSCs in gliomas and in the abnomal expression of miRNAs in GSCs. Furthermore, we also discuss epigenetic dysregulation of tumor-suppressor miRNAs by promoter DNA methylation is involved in the regulation of GSCs biology. Recent advances in understanding dysregulated expression of miRNAs and methylation of tumor-suppressor miRNAs in GSCs and their possible use as new therapeutic targets of gliomas.
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Neoplasias Encefálicas/metabolismo , Metilação de DNA , Glioma/metabolismo , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neurais/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Metilação de DNA/efeitos dos fármacos , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Humanos , MicroRNAs/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Regiões Promotoras GenéticasRESUMO
DNA methylation at the 5-position of cytosine (5mC) in the mammalian genome has emerged as a pivotal epigenetic event that plays important roles in development, aging and disease. The three members of the TET protein family, which convert 5mC to 5-hydroxymethylcytosine, has provided a potential mechanism resulting in DNA demethylation and maintaining cellular identity. Recent studies have shown that epigenetic modifications play a key role in the regulation of the molecular pathogenesis of gliomas. In this review we focus on demonstrating the TET proteins in DNA demethylation and transcriptional regulation of different target genes. In addition, we address the role of TET proteins in gliomas. This review will provide valuable insights into the potential targets of gliomas, and may open the possibility of novel therapeutic approaches to this fatal disease.
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Neoplasias Encefálicas/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioma/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Metilação de DNA , Proteínas de Ligação a DNA , Dioxigenases , Humanos , Oxigenases de Função MistaRESUMO
GPR137 are ubiquitously expressed in the central nervous system. However, the role o f GPR137 in human malignant glioma is still poorly known. In the present study, we firstly detected the expression of GPR137 in 29 human glioma tissue specimens by immunohistochemistry and in 5 malignant glioma cell lines by quantitative RT-PCR. The expression of GPR137 was much stronger in high-grade gliomas than in low-grade gliomas. Lentivirus-mediated small interfering RNAs (siRNAs) were employed to knock down GPR137 expression in glioma cells. Inhibition of GPR137 expression by RNAi significantly inhibited the proliferation and colony-forming capacity of U251, A172 and U373 cells. Moreover, flow cytometry analysis showed that knockdown of GPR137 led to the cell-cycle arrest at the S phase. Our results indicated that GPR137 is involved in the progression of human glioma, suggesting GPR137 as a potential oncogene of glioma cells.
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Neoplasias Encefálicas/patologia , Glioma/patologia , Receptores Acoplados a Proteínas G/metabolismo , Western Blotting , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Osteosarcoma (OS) is a heterogeneous malignant spindle cell tumor that is aggressive and has a poor prognosis. Although combining surgery and chemotherapy has significantly improved patient outcomes, the prognosis for OS patients with metastatic or recurrent OS has remained unsatisfactory. Therefore, it is imperative to gain a fresh perspective on OS development mechanisms and treatment strategies. After studying single-cell RNA sequencing (scRNA-seq) data in public databases, we identified seven OS subclonal types based on intra-tumor heterogeneity. Subsequently, we constructed a prognostic model based on pro-protein synthesis osteosarcoma (PPS-OS)-associated genes. Correlation analysis showed that the prognostic model performs extremely well in predicting OS patient prognosis. We also demonstrated that the independent risk factors for the prognosis of OS patients were tumor primary site, metastatic status, and risk score. Based on these factors, nomograms were constructed for predicting the 3- and 5-year survival rates. Afterward, the investigation of the tumor immune microenvironment (TIME) revealed the vital roles of γδ T-cell and B-cell activation. Drug sensitivity analysis and immune checkpoint analysis identified drugs that have potential application value in OS. Finally, the jumping translocation breakpoint (JTB) gene was selected for experimental validation. JTB silencing suppressed the proliferation, migration, and invasion of OS cells. Therefore, our research suggests that PPS-OS-related genes facilitate the malignant progression of OS and may be employed as prognostic indicators and therapeutic targets in OS.
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Neoplasias Ósseas , Osteossarcoma , Microambiente Tumoral , Humanos , Osteossarcoma/genética , Osteossarcoma/terapia , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Osteossarcoma/mortalidade , Osteossarcoma/tratamento farmacológico , Prognóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/terapia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/tratamento farmacológico , Feminino , Masculino , Regulação Neoplásica da Expressão Gênica , Nomogramas , Linhagem Celular Tumoral , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de CélulasRESUMO
Gliomas are the most common type of primary brain tumor. Despite advances in treatment, it remains one of the most aggressive and deadly tumor of the central nervous system (CNS). Gliomas are characterized by high malignancy, heterogeneity, invasiveness, and high resistance to radiotherapy and chemotherapy. It is urgent to find potential new molecular targets for glioma. The TRPM channels consist of TRPM1-TPRM8 and play a role in many cellular functions, including proliferation, migration, invasion, angiogenesis, etc. More and more studies have shown that TRPM channels can be used as new therapeutic targets for glioma. In this review, we first introduce the structure, activation patterns, and physiological functions of TRPM channels. Additionally, the pathological mechanism of glioma mediated by TRPM2, 3, 7, and 8 and the related signaling pathways are described. Finally, we discuss the therapeutic potential of targeting TRPM for glioma.
â¢TRPM channels are widely expressed in the human body and play an important role in gliomas.⢠Abnormal expression of TRPM2, 3, 7, and 8 channels in gliomas is associated with disease severity and prognosis.â¢TRPM2, 3, 7, and 8 channels are effective targets in glioma.
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Neoplasias Encefálicas , Glioma , Canais de Cátion TRPM , Humanos , Glioma/metabolismo , Glioma/patologia , Glioma/genética , Glioma/tratamento farmacológico , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPM/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Transdução de Sinais , AnimaisRESUMO
Osteosarcoma, one of the most common primary malignancies in children and adolescents, has the primary characteristics of a poor prognosis and high rate of metastasis. This study used super-enhancer-related genes derived from two different cell lines to construct five novel super-enhancer-related gene prognostic models for patients with osteosarcoma. The training and testing datasets were used to confirm the prognostic models of the five super-enhancer-related genes, which resulted in an impartial predictive element for osteosarcoma. The immunotherapy and prediction of the response to anticancer drugs have shown that the risk signature of the five super-enhancer-related genes positively correlate with chemosensitivity. Furthermore, functional analysis of the risk signature genes revealed a significant relationship between gene groups and the malignant characteristics of tumours. TNF Receptor Superfamily Member 11b (TNFRSF11B) was selected for functional verification. Silencing of TNFRSF11B suppressed the proliferation, migration, and invasion of osteosarcoma cells in vitro and suppressed osteosarcoma growth in vivo. Moreover, transcriptome sequencing was performed on MG-63 cells to study the regulatory mechanism of TNFRSF11B in osteosarcoma cells, and it was discovered that TNFRSF11B is involved in the development of osteosarcoma via the phosphoinositide 3-kinase signalling pathway. Following the identification of TNFRSF11B as a key gene, we selected an inhibitor that specifically targeted this gene and performed molecular docking simulations. In addition, risedronic acid inhibited osteosarcoma growth at both cellular and molecular levels. In conclusion, the super-enhancer-related gene signature is a viable therapeutic tool for osteosarcoma prognosis and treatment.
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BACKGROUND: The mesenchymal (MES) subtype of glioblastoma (GBM) is believed to be influenced by both cancer cell-intrinsic alterations and extrinsic cellular interactions, yet the underlying mechanisms remain unexplored. METHODS: Identification of microglial heterogeneity by bioinformatics analysis. Transwell migration, invasion assays, and tumor models were used to determine gene function and the role of small molecule inhibitors. RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays were performed to explore the underlying regulatory mechanisms. RESULTS: We identified the inflammatory microglial subtype of tumor-associated microglia (TAM) and found that its specific gene integrin beta 2 (ITGB2) was highly expressed in TAM of MES GBM tissues. Mechanistically, the activation of ITGB2 in microglia promoted the interaction between the SH2 domain of STAT3 and the cytoplasmic domain of ITGB2, thereby stimulating the JAK1/STAT3/IL-6 signaling feedback to promote the MES transition of GBM cells. Additionally, microglia communicated with GBM cells through the interaction between the receptor ITGB2 on microglia and the ligand ICAM-1 on GBM cells, while an increased secretion of ICAM-1 was induced by the proinflammatory cytokine leukemia inhibitory factor (LIF). Further studies demonstrated that inhibition of cyclin-dependent kinase 7 substantially reduced the recruitment of SNW1 to the super-enhancer of LIF, resulting in transcriptional inhibition of LIF. We identified notoginsenoside R1 as a novel LIF inhibitor that exhibited synergistic effects in combination with temozolomide. CONCLUSIONS: Our research reveals that the epigenetic-mediated interaction of GBM cells with TAM drives the MES transition of GBM and provides a novel therapeutic avenue for patients with MES GBM.