Identification of prognostic biomarker of non-small cell lung cancer based on mitochondrial permeability transition-driven necrosis-related genes and determination of anti-tumor effect of ARL14.

IF 2.7 3区 生物学
Zhifei Ma, Wen Chen, Aiping Zhang, Xiaokang Shen, Lin Zheng
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引用次数: 0

Abstract

Background: Mitochondrial permeability transition (MPT)-driven necrosis (MPTDN) is a non-apoptotic mode of cell death triggered by oxidative stress and cytosolic Ca2+ overload. Recent evidence suggests that activation of MPTND can effectively induce cancer cell death and may represent a novel therapeutic strategy for cancer. Yet, the role of MPTDN-related genes in non-small cell lung cancer (NSCLC) remains unrevealed. This study aimed to identify MPTDN-related biomarkers for predicting prognosis and guiding treatment in NSCLC.

Methods: Gene expression profiles and clinical information of NSCLC were collected from public databases, and MPTDN-related genes were obtained from published article. Differential expressed MPTDN-related genes in NSCLC and control were screened, and molecular clusters were obtained. Based on the differentially expressed genes (DGEs) between clusters, univariate Cox and LASSO regression analyses were performed to screen biomarkers, followed by nomogram construction. Correlations between these biomarkers and immune cell infiltration, immune checkpoints, and chemotherapeutic agents were observed. Expression levels of MPTDN-related biomarkers were detected using RT-qPCR in NSCLC tissues and cells. Moreover, the biological function of ARL14 in NSLCL was verified in vitro.

Results: Thirty-five differential MPTDN-related genes were identified, and two molecular clusters were obtained. Three biomarkers with prognostic values were finally screened, including ARL14, ZDHHC11B, and HLF. Among them, ARL14 was significantly upregulated in tumor samples, while ZDHHC11B and HLF were downregulated. Nomogram containing three genes exhibited predictive accuracy in 1, 3, and 5-year survival rates. Three gene were strongly associated with most immune cells, immune checkpoints, and drugs sensitivity. RT-qPCR confirmed that expression levels of three genes in tissues or cells were consistent with the results of bioinformatics analysis. Finally, ARL14 knockdown inhibited the malignant phenotype of NSCLC cells.

Conclusion: We first performed the comprehensive analysis of MPTDN in NSCLC and screened three NSCLC-related biomarkers as promising biomarkers. ARL14 might be a new potential target for therapy of NSCLC.

基于线粒体通透性过渡驱动的坏死相关基因鉴定非小细胞肺癌预后生物标志物及ARL14抗肿瘤作用的测定
背景:线粒体通透性转变(MPT)驱动的坏死(MPTDN)是一种由氧化应激和细胞质Ca2+过载引发的非凋亡细胞死亡模式。最近的证据表明,激活MPTND可以有效地诱导癌细胞死亡,可能是一种新的癌症治疗策略。然而,mptdn相关基因在非小细胞肺癌(NSCLC)中的作用仍未被揭示。本研究旨在寻找与mptdn相关的生物标志物,用于预测非小细胞肺癌的预后和指导治疗。方法:从公共数据库中收集NSCLC的基因表达谱和临床信息,从已发表的文章中获取mptdn相关基因。筛选mptdn相关基因在NSCLC和对照组中差异表达,获得分子簇。基于聚类间差异表达基因(DGEs),采用单变量Cox和LASSO回归分析筛选生物标志物,并进行nomogram构建。观察了这些生物标志物与免疫细胞浸润、免疫检查点和化疗药物之间的相关性。采用RT-qPCR检测mptdn相关生物标志物在NSCLC组织和细胞中的表达水平。此外,ARL14在NSLCL中的生物学功能也得到了体外验证。结果:鉴定出35个mptdn差异相关基因,获得2个分子簇。最终筛选出3个具有预后价值的生物标志物,包括ARL14、ZDHHC11B和HLF。其中,ARL14在肿瘤样本中显著上调,ZDHHC11B和HLF下调。包含三个基因的Nomogram预测1、3、5年生存率的准确性。三个基因与大多数免疫细胞、免疫检查点和药物敏感性密切相关。RT-qPCR证实了三个基因在组织或细胞中的表达水平与生物信息学分析结果一致。最后,ARL14敲低抑制了NSCLC细胞的恶性表型。结论:我们首先进行了MPTDN在NSCLC中的综合分析,筛选出3种NSCLC相关的生物标志物作为有前景的生物标志物。ARL14可能是治疗非小细胞肺癌的一个新的潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Hereditas
Hereditas Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
3.80
自引率
3.70%
发文量
0
期刊介绍: For almost a century, Hereditas has published original cutting-edge research and reviews. As the Official journal of the Mendelian Society of Lund, the journal welcomes research from across all areas of genetics and genomics. Topics of interest include human and medical genetics, animal and plant genetics, microbial genetics, agriculture and bioinformatics.
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