A TGF-β signaling-related lncRNA signature for prediction of glioma prognosis, immune microenvironment, and immunotherapy response

IF 4.8 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2023-10-18 DOI:10.1111/cns.14489

Wei-Wei Duan, Li-Ting Yang, Jian Liu, Zi-Yu Dai, Ze-Yu Wang, Hao Zhang, Xun Zhang, Xi-Song Liang, Peng Luo, Jian Zhang, Zao-Qu Liu, Nan Zhang, Hao-Yang Mo, Chun-Run Qu, Zhi-Wei Xia, Quan Cheng

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Abstract

Aims

The dysregulation of TGF-β signaling is a crucial pathophysiological process in tumorigenesis and progression. LncRNAs have diverse biological functions and are significant participants in the regulation of tumor signaling pathways. However, the clinical value of lncRNAs related to TGF-β signaling in glioma is currently unclear.

Methods

Data on glioma's RNA-seq transcriptome, somatic mutation, DNA methylation data, and clinicopathological information were derived from the CGGA and TCGA databases. A prognostic lncRNA signature was constructed by Cox and LASSO regression analyses. TIMER2.0 database was utilized to deduce immune infiltration characteristics. “ELMER v.2” was used to reconstruct TF-methylation-gene regulatory network. Immunotherapy and chemotherapy response predictions were implemented by the TIDE algorithm and GDSC database, respectively. In vitro and in vivo experiments were conducted to verify the results and clarify the regulatory mechanism of lncRNA.

Results

In glioma, a TGF-β signaling-related 15-lncRNA signature was constructed, including AC010173.1, HOXA-AS2, AC074286.1, AL592424.1, DRAIC, HOXC13-AS, AC007938.1, AC010729.1, AC013472.3, AC093895.1, AC131097.4, AL606970.4, HOXC-AS1, AGAP2-AS1, and AC002456.1. This signature proved to be a reliable prognostic tool, with high risk indicating an unfavorable prognosis and being linked to malignant clinicopathological and genomic mutation traits. Risk levels were associated with different immune infiltration landscapes, where high risk was indicative of high levels of macrophage infiltration. In addition, high risk also suggested better immunotherapy and chemotherapy response. cg05987823 was an important methylation site in glioma progression, and AP-1 transcription factor family participated in the regulation of signature lncRNA expression. AGAP2-AS1 knockdown in in vitro and in vivo experiments inhibited the proliferation, migration, and invasion of glioma cells, as well as the growth of glioma, by downregulating the expression levels of NF-κB and ERK 1/2 in the TGF-β signaling pathway.

Conclusions

A prognostic lncRNA signature of TGF-β signaling was established in glioma, which can be used for prognostic judgment, immune infiltration status inference, and immunotherapy response prediction. AGAP2-AS1 plays an important role in glioma progression.

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用于预测神经胶质瘤预后、免疫微环境和免疫治疗反应的TGF-β信号传导相关lncRNA信号。

目的：TGF-β信号传导的失调是肿瘤发生和发展的重要病理生理过程。lncRNA具有多种生物学功能，是肿瘤信号通路调控的重要参与者。然而，与TGF-β信号传导相关的lncRNA在神经胶质瘤中的临床价值目前尚不清楚。方法：从CGGA和TCGA数据库中获得神经胶质瘤RNA-seq转录组、体细胞突变、DNA甲基化数据和临床病理信息。Cox和LASSO回归分析构建了预后lncRNA信号。TIMER2.0数据库用于推断免疫浸润特征。用“ELMER v.2”构建TF甲基化基因调控网络。免疫治疗和化疗反应预测分别通过TIDE算法和GDSC数据库实现。结果：在胶质瘤中，构建了TGF-β信号相关的15 lncRNA信号，包括AC010173.1、HOXA-AS2、AC074286.1、AL592424.1、DRAIC、HOXC13-AS、AC007938.1、AC010729.1、AC013472.3、AC093895.1、AC131097.4、AL606970.4、HOXC-AS1、AGAP2-AS1和AC002456.1。该特征被证明是一种可靠的预后工具，高风险表明预后不良，并与恶性临床病理和基因组突变特征有关。风险水平与不同的免疫浸润景观有关，其中高风险表明巨噬细胞浸润水平高。此外，高风险还表明免疫疗法和化疗反应更好。cg05987823是胶质瘤进展中一个重要的甲基化位点，AP-1转录因子家族参与了标志性lncRNA表达的调控。AGAP2-AS1在体外和体内敲除实验中通过下调TGF-β信号通路中NF-κB和ERK1/2的表达水平，抑制神经胶质瘤细胞的增殖、迁移和侵袭，以及神经胶质瘤的生长。结论：在胶质瘤中建立了TGF-β信号的预后lncRNA标记，可用于预后判断、免疫浸润状态推断和免疫治疗反应预测。AGAP2-AS1在胶质瘤的进展中起着重要作用。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.