Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma.

IF 5.7 2区 医学 Q1 Medicine
Yongbiao Huang, Lingyan Xiao, Motuma Yigezu Daba, Duo Xu, Yuan Wang, Long Li, Qian Li, Bo Liu, Wan Qin, Huixian Zhang, Xianglin Yuan
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引用次数: 0

Abstract

Background: Chromatin regulators (CRs) are critical epigenetic modifiers and have been reported to play critical roles during the progression of various tumors, but their role in lung adenocarcinoma (LUAD) has not been comprehensively studied.

Methods: Differential expression and univariate Cox regression analyses were conducted to identify the prognostic CRs. Consensus clustering was applied to classify the subtypes of LUAD based on prognostic CRs. LASSO-multivariate Cox regression method was used for construction of a prognostic signature and development of chromatin regulator-related gene index (CRGI). The capacity of CRGI to distinguish survival was evaluated via Kaplan-Meier method in multiple datasets. Relationship between CRGI and tumor microenvironment (TME) was evaluated. Additionally, clinical variables and CRGI were incorporated to create a nomogram. The role of the prognostic gene NPAS2 in LUAD was elucidated via clinical samples validation and a series of in vitro and in vivo experiments.

Results: Two subtypes of LUAD were classified based on 46 prognostic CRs via consensus clustering which had significantly different survival and TME. A prognostic signature consisting of six CRs (MOCS, PBK, CBX3, A1CF, NPAS2, and CTCFL) was developed and proved to be an effective survival predictor in multiple independent datasets. The prognostic signature was also demonstrated to be an indicator of TME and sensitivity to immunotherapy and chemotherapy. The nomogram was suggested to be a simple tool that can predict survival accurately. Clinical samples show that NPAS2 is highly expressed in LUAD tissues, and in vitro and in vivo experiments demonstrated that inhibition of NPAS2 impeded malignant progression of LUAD cells.

Conclusions: Our study comprehensively unveiled the functions of CRs in LUAD, developed a classifier to predict survival and response to treatments, and suggested that NPAS2 promoted LUAD progression for the first time.

Abstract Image

Abstract Image

Abstract Image

基于染色质调控因子的分子亚型特征和NPAS2在肺腺癌中的作用鉴定。
背景:染色质调节因子(CRs)是一种重要的表观遗传修饰因子,在各种肿瘤的进展过程中发挥着重要作用,但其在肺腺癌(LUAD)中的作用尚未得到全面研究。方法:采用差异表达和单因素Cox回归分析,确定预后cr。基于预后cr,采用共识聚类对LUAD亚型进行分类。采用lasso -多变量Cox回归方法构建预后标记并开发染色质调控因子相关基因指数(CRGI)。通过Kaplan-Meier方法在多个数据集中评估CRGI区分生存的能力。评价CRGI与肿瘤微环境(TME)的关系。此外,临床变量和CRGI被纳入创建一个nomogram。预后基因NPAS2在LUAD中的作用通过临床样本验证和一系列体外和体内实验得以阐明。结果:基于46个预后cr,通过共识聚类将LUAD分为两种亚型,其生存期和TME有显著差异。研究人员开发了一个由6个cr (MOCS、PBK、CBX3、A1CF、NPAS2和CTCFL)组成的预后特征,并在多个独立数据集中证明了它是一个有效的生存预测指标。预后特征也被证明是TME和对免疫治疗和化疗敏感性的指标。nomogram是一种简单的预测生存率的方法。临床样本显示,NPAS2在LUAD组织中高表达,体外和体内实验表明,抑制NPAS2可阻碍LUAD细胞的恶性进展。结论:我们的研究全面揭示了CRs在LUAD中的功能,开发了一种预测生存和治疗反应的分类器,并首次提示NPAS2促进LUAD进展。
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
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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