Development and Validation of a Cholesterol-related Gene Signature for Prognostic Assessment in Head and Neck Squamous Cell Carcinoma.

IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jiarong Zheng, Dalong Shu, Rongwei Xu, Yucheng Zheng, Pei Lin, Yunfan Lin, Xinyuan Zhao, Li Cui, Xin Liao, Bing Guo
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引用次数: 0

Abstract

Aim: This study seeks to develop a prognostic risk signature for head and neck squamous cell carcinoma (HNSCC) based on cholesterol-related genes (CholRG), aiming to enhance prognostic accuracy in clinical practice.

Background: HNSCC poses significant challenges due to its aggressive behavior and limited response to standard treatments, resulting in elevated morbidity and mortality rates.In order to improve prognostic prediction in HNSCC, our study is inspired by the realization that cholesterol metabolism plays a critical role in accelerating the progression of cancer. To this end, we are developing a unique risk signature using CholRG.

Objective: The aim of this study was to create a CholRG-based risk signature to predict HNSCC prognosis, aiding in clinical decision-making accurately.

Method: The TCGA HNSCC dataset, along with GSE41613 and GSE65858, was obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, respectively. A CholRG-based risk signature was then developed and validated across various independent HNSCC cohorts. Moreover, a nomogram model incorporating CholRG-based risk signature was established. Additionally, functional enrichment analysis was conducted, and the immune landscapes of the high- and low-risk groups were compared. Finally, in vitro experiments were performed using lipid-based transfection to deliver siRNAs targeting ACAT1 to SCC1 and SCC23 cell lines, further examining the effects of ACAT1 knockdown on these cells.

Results: Utilizing RNA-seq, microarray, and clinical data from public databases, we constructed and validated a CholRG-based risk signature that includes key genes such as ACAT1, CYP19A1, CYP27A1, FAXDC2, INSIG2, PRKAA2, and SEC14L2, which can effectively predict the clinical outcome of HNSCC. Additionally, our findings were reinforced by a nomogram model that integrates the risk score with clinical variables for more clinically practical prognostic assessment. In addition, patients at high risk show hypoxia and increased oncogenic pathways such as mTORC1 signaling, as well as a suppressed immune microenvironment marked by a reduction in the infiltration of important immune cells. Notably, in vitro experiments showed that ACAT1 depletion significantly suppressed the proliferation, colony formation, and invasion capabilities of HNSCC cells, confirming ACAT1's role in promoting malignancy.

Conclusion: Collectively, our study not only underscores the importance of cholesterol metabolism in HNSCC pathogenesis but also highlights the CholRG-based risk signature as a promising tool for enhancing prognostic accuracy and personalizing therapeutic strategies.

用于头颈部鳞状细胞癌预后评估的胆固醇相关基因特征的开发与验证
目的:本研究旨在开发基于胆固醇相关基因(CholRG)的头颈部鳞状细胞癌(HNSCC)预后风险特征,以提高临床实践中预后的准确性:为了改善 HNSCC 的预后预测,我们的研究受到了胆固醇代谢在加速癌症进展中发挥关键作用这一认识的启发。为此,我们正在利用 CholRG 开发一种独特的风险特征:本研究的目的是创建一个基于胆固醇代谢的风险特征来预测 HNSCC 的预后,从而准确地帮助临床决策:方法:TCGA HNSCC数据集以及GSE41613和GSE65858分别来自癌症基因组图谱(TCGA)和基因表达总库(GEO)数据库。然后开发了基于 CholRG 的风险特征,并在多个独立的 HNSCC 队列中进行了验证。此外,还建立了一个包含基于 CholRG 风险特征的提名图模型。此外,还进行了功能富集分析,并比较了高风险组和低风险组的免疫图谱。最后,利用脂质转染技术将靶向 ACAT1 的 siRNA 运送到 SCC1 和 SCC23 细胞系中,进行了体外实验,进一步研究了 ACAT1 基因敲除对这些细胞的影响:利用RNA-seq、微阵列和来自公共数据库的临床数据,我们构建并验证了基于CholRG的风险特征,其中包括ACAT1、CYP19A1、CYP27A1、FAXDC2、INSIG2、PRKAA2和SEC14L2等关键基因,这些基因可以有效预测HNSCC的临床结果。此外,我们的研究结果还得到了一个提名图模型的支持,该模型将风险评分与临床变量结合在一起,以进行更具临床实用性的预后评估。此外,高风险患者表现出缺氧和致癌通路(如 mTORC1 信号转导)的增加,以及免疫微环境的抑制,其特点是重要免疫细胞的浸润减少。值得注意的是,体外实验显示,ACAT1的缺失显著抑制了HNSCC细胞的增殖、集落形成和侵袭能力,证实了ACAT1在促进恶性肿瘤中的作用:总之,我们的研究不仅强调了胆固醇代谢在 HNSCC 发病机制中的重要性,还突出了基于 CholRG 的风险特征是提高预后准确性和个性化治疗策略的有效工具。
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来源期刊
Current medicinal chemistry
Current medicinal chemistry 医学-生化与分子生物学
CiteScore
8.60
自引率
2.40%
发文量
468
审稿时长
3 months
期刊介绍: Aims & Scope Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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