Integrative analysis of a novel super-enhancer-associated lncRNA prognostic signature and identifying LINC00945 in aggravating glioma progression.

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.

Single-Cell RNA Sequencing Pro-angiogenic Macrophage Profiles Reveal Novel Prognostic Biomarkers and Therapeutic Targets for Osteosarcoma.

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.

A Novel Defined Necroptosis-Related Genes Prognostic Signature for Predicting Prognosis and Treatment of Osteosarcoma.

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.

DNMT1 Mediated CAHM Repression Promotes Glioma Invasion via SPAK/JNK Pathway.

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.

Identification of an endoplasmic reticulum stress-related signature associated with clinical prognosis and immune therapy in glioma.

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.

NLRC5 negatively regulates inflammatory responses in LPS-induced acute lung injury through NF-κB and p38 MAPK signal pathways.

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.

LncRNA-ATB in cancers: what do we know so far?

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.

IFITM3/STAT3 axis promotes glioma cells invasion and is modulated by TGF-ß.

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.

New advances of lncRNAs in liver fibrosis, with specific focus on lncRNA-miRNA interactions.

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.

LncRNA-ATB promotes TGF-ß-induced glioma cells invasion through NF-κB and P38/MAPK pathway.

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.

Hotair facilitates hepatic stellate cells activation and fibrogenesis in the liver.

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.

LncRNAs: new players in gliomas, with special emphasis on the interaction of lncRNAs With EZH2.

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.

New advances of microRNAs in glioma stem cells, with special emphasis on aberrant methylation of microRNAs.

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.

TET family proteins: new players in gliomas.

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.

Inhibition of GPR137 expression reduces the proliferation and colony formation of malignant glioma cells.

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.

Roles of TRPM channels in glioma.

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.

•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.•TRPM2, 3, 7, and 8 channels are effective targets in glioma.

Super-enhancer-driven LIF promotes the mesenchymal transition in glioblastoma by activating ITGB2 signaling feedback in microglia.

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 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 LIF. Further studies demonstrated that inhibition of CDK7 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.

Self-Assembled Aza-Boron-Dipyrromethene-Based H2S Prodrug for Synergistic Ferroptosis-Enabled Gas and Sonodynamic Tumor Therapies.

Glioblastoma multiforme (GBM) is the most aggressive and lethal subtype of gliomas of the central nervous system. The efficacy of sonodynamic therapy (SDT) against GBM is significantly reduced by the expression of apoptosis-inhibitory proteins in GBM cells. In this study, an intelligent nanoplatform (denoted as Aza-BD@PC NPs) based on the aza-boron-dipyrromethene dye and phenyl chlorothionocarbonate-modified DSPE-PEG molecules is developed for synergistic ferroptosis-enabled gas therapy (GT) and SDT of GBM. Once internalized by GBM cells, Aza-BD@PC NPs showed effective cysteine (Cys) consumption and Cys-triggered hydrogen sulfide (H2S) release for ferroptosis-enabled GT, thereby disrupting homeostasis in the intracellular environment, affecting GBM cell metabolism, and inhibiting GBM cell proliferation. Additionally, the released Aza-BD generated abundant singlet oxygen (1O2) under ultrasound irradiation for favorable SDT. In vivo and in vitro evaluations demonstrated that the combined functions of Cys consumption, H2S production, and 1O2 production induced significant death of GBM cells and markedly inhibited tumor growth, with an impressive inhibition rate of up to 97.5%. Collectively, this study constructed a cascade nanoreactor with satisfactory Cys depletion performance, excellent H2S release capability, and prominent reactive oxygen species production ability under ultrasound irradiation for the synergistic ferroptosis-enabled GT and SDT of gliomas.

PIWI-interacting RNAs: Critical roles and therapeutic targets in cancer.

P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a novel class of small regulatory RNAs (approximately 24-31 nucleotides in length) that often bind to members of the PIWI protein family. piRNAs regulate transposons in animal germ cells; piRNAs are also specifically expressed in many human tissues and regulate pivotal signaling pathways. Additionally, the abnormal expression of piRNAs and PIWI proteins has been associated with various malignant tumours, and multiple mechanisms of piRNA-mediated target gene dysregulation are involved in tumourigenesis and progression, suggesting that they have the potential to serve as new biomarkers and therapeutic targets for tumours. However, the functions and potential mechanisms of action of piRNAs in cancer have not yet been elucidated. This review summarises the current findings on the biogenesis, function, and mechanisms of piRNAs and PIWI proteins in cancer. We also discuss the clinical significance of piRNAs as diagnostic or prognostic biomarkers and therapeutic tools for cancer. Finally, we present some critical questions regarding piRNA research that need to be addressed to provide insight into the future development of the field.

Super-enhancers complexes zoom in transcription in cancer.

Super-enhancers (SEs) consist of multiple typical enhancers enriched at high density with transcription factors, histone-modifying enzymes and cofactors. Oncogenic SEs promote tumorigenesis and malignancy by altering protein-coding gene expression and noncoding regulatory element function. Therefore, they play central roles in the treatment of cancer. Here, we review the structural characteristics, organization, identification, and functions of SEs and the underlying molecular mechanism by which SEs drive oncogenic transcription in tumor cells. We then summarize abnormal SE complexes, SE-driven coding genes, and noncoding RNAs involved in tumor development. In summary, we believe that SEs show great potential as biomarkers and therapeutic targets.