Dataset Information

Identification of RP11-770J1.4 as immune-related lncRNA regulating the CTXN1-cGAS-STING axis in histologically lower-grade glioma.

ABSTRACT: Human gliomas are lethal brain cancers. Emerging evidence revealed the regulatory role of long noncoding RNAs (lncRNAs) in tumors. Here, we performed a comprehensive analysis of the expression profiles of RNAs in histologically lower-grade glioma (LGG). Enrichment analysis revealed that glioma is influenced by immune-related signatures. Survival analysis further established the close correlation between network features and glioma prognosis. Subsequent experiments showed lncRNA RP11-770J1.4 regulates CTXN1 expression through hsa-miR-124-3p. Correlation analysis identified lncRNA RP11-770J1.4 was immune related, specifically involved in the cytosolic DNA sensing pathway. Downregulated lncRNA RP11-770J1.4 resulted in increased spontaneous gene expression of the cGAS-STING pathway. Single-cell RNA sequencing analysis, along with investigations in a glioblastoma stem cell model and patient sample analysis, demonstrated the predominant localization of CTXN1 within tumor cores rather than peripheral regions. Immunohistochemistry staining established a negative correlation between CTXN1 expression and infiltration of CD8⁺ T cells. In vivo, Ctxn1 knockdown in GL261 cells led to decreased tumor burden and improved survival while increasing infiltration of CD8⁺ T cells. These findings unveil novel insights into the lncRNA RP11-770J1.4-CTXN1 as a potential immune regulatory axis, highlighting its therapeutic implications for histologically LGGs.

SUBMITTER: Zhuang Q

PROVIDER: S-EPMC10728758 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Identification of RP11-770J1.4 as immune-related lncRNA regulating the CTXN1-cGAS-STING axis in histologically lower-grade glioma.

Zhuang Qiyuan Q Liu Chaxian C Hu Yihan Y Liu Ying Y Lyu Yingying Y Liao Yuheng Y Chen Liang L Yang Hui H Mao Ying Y

MedComm 20231219 6

Human gliomas are lethal brain cancers. Emerging evidence revealed the regulatory role of long noncoding RNAs (lncRNAs) in tumors. Here, we performed a comprehensive analysis of the expression profiles of RNAs in histologically lower-grade glioma (LGG). Enrichment analysis revealed that glioma is influenced by immune-related signatures. Survival analysis further established the close correlation between network features and glioma prognosis. Subsequent experiments showed lncRNA RP11-770J1.4 regu ...[more]

PMID: 38116063

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Project description:BackgroundThe expression of long non-coding RNA (lncRNA) prostate cancer-associated ncRNA transcripts 1 (PCAT1) is increased in non-small cell lung cancer (NSCLC). It stimulates tumour growth and metastasis, but its role in the radioimmune responses remain unknown. We aimed to explore the impacts of PCAT1 on tumorigenesis and radioimmune responses and the underlying molecular mechanisms in NSCLC.MethodsComprehensive bioinformatics analysis was performed to identify immunosuppressive lncRNAs involved with tumour invasion in NSCLC. The expression levels of PCAT1 were analysed by in situ hybridisation in 55 paired NSCLC tissues and adjacent normal tissues. Both loss- and gain-of-function assays were performed to examine the effects of PCAT1 and SOX2 on NSCLC cell behaviours in vivo and in vitro. Bioinformatic analyses, chromatin isolation by RNA purification (ChIRP) and dual-luciferase reporter assays were applied to validate the regulatory effects of PCAT1 on SOX2 expression. Chromatin immunoprecipitation, luciferase and rescue assays were utilised to identify the relationship between SOX2 and the cGAS/stimulator of interferon genes (STING) signalling.ResultsPCAT1 was immunosuppressive and related with NSCLC invasion. Increased PCAT1 was negatively correlated with immune cell infiltration in NSCLC. PCAT1 knockdown restrained proliferation, increased apoptosis, and repressed cell metastasis in vivo and in vitro. PCAT1 activated SOX2 that accelerated tumorigenesis and immunosuppression. SOX2 promoted tumour growth through inhibiting cytotoxic T-cell immunity. Moreover, SOX2 restrained cGAS transcription and hampered downstream type I interferon (IFN)-induced immune responses. Inhibition of PCAT1/SOX2 in collaboration with radiation further inhibited tumour growth, and initiated the cGAS/STING signalling pathway, which enhanced the immune responses of radiotherapy in NSCLC.ConclusionsPCAT1/SOX2 axis promoted tumorigenesis and immunosuppression through inhibition of cGAS/STING signalling-mediated T-cell activation. Inhibition of PCAT1 and SOX2 synergised with radiotherapy to activate the immune response and could serve as potential therapeutic targets.

Project description:Energy metabolic processes play important roles for tumor malignancy, indicating that related protein-coding genes and regulatory upstream genes (such as long noncoding RNAs (lncRNAs)) may represent potential biomarkers for prognostic prediction. This study will develop a new energy metabolism-related lncRNA-mRNA prognostic signature for lower-grade glioma (LGG) patients. A GSE4290 dataset obtained from Gene Expression Omnibus was used for screening the differentially expressed genes (DEGs) and lncRNAs (DELs). The Cancer Genome Atlas (TCGA) dataset was used as the prognosis training set, while the Chinese Glioma Genome Atlas (CGGA) was for the validation set. Energy metabolism-related genes were collected from the Molecular Signatures Database (MsigDB), and a coexpression network was established between energy metabolism-related DEGs and DELs to identify energy metabolism-related DELs. Least absolute shrinkage and selection operator (LASSO) analysis was performed to filter the prognostic signature which underwent survival analysis and nomogram construction. A total of 1613 DEGs and 37 DELs were identified between LGG and normal brain tissues. One hundred and ten DEGs were overlapped with energy metabolism-related genes. Twenty-seven DELs could coexpress with 67 metabolism-related DEGs. LASSO regression analysis showed that 9 genes in the coexpression network were the optimal signature and used to construct the risk score. Kaplan-Meier curve analysis showed that patients with a high risk score had significantly worse OS than those with a low risk score (TCGA: HR = 3.192, 95%CI = 2.182-4.670; CGGA: HR = 1.922, 95%CI = 1.431-2.583). The predictive accuracy of the risk score was also high according to the AUC of the ROC curve (TCGA: 0.827; CGGA: 0.806). Multivariate Cox regression analyses revealed age, IDH1 mutation, and risk score as independent prognostic factors, and thus, a prognostic nomogram was established based on these three variables. The excellent prognostic performance of the nomogram was confirmed by calibration and discrimination analyses. In conclusion, our findings provided a new biomarker for the stratification of LGG patients with poor prognosis.

Dataset Information

Identification of RP11-770J1.4 as immune-related lncRNA regulating the CTXN1-cGAS-STING axis in histologically lower-grade glioma.

Publications

Identification of RP11-770J1.4 as immune-related lncRNA regulating the CTXN1-cGAS-STING axis in histologically lower-grade glioma.

Similar Datasets

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