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脂质代谢相关基因 PTGIS 和 HRASLS 对肺鳞癌表型、预后和肿瘤免疫的影响。

Effects of Lipid Metabolism-Related Genes PTGIS and HRASLS on Phenotype, Prognosis, and Tumor Immunity in Lung Squamous Cell Carcinoma.

机构信息

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

出版信息

Oxid Med Cell Longev. 2023 Jan 17;2023:6811625. doi: 10.1155/2023/6811625. eCollection 2023.

DOI:10.1155/2023/6811625
PMID:36703911
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9873467/
Abstract

BACKGROUND: Lipid metabolism reprogramming played an important role in cancer occurrence, development, and immune regulation. The aim of this study was to identify and validate lipid metabolism-related genes (LMRGs) associated with the phenotype, prognosis, and immunological characteristics of lung squamous cell carcinoma (LUSC). METHODS: In the TCGA cohort, bioinformatics and survival analysis were used to identify lipid metabolism-related differentially expressed genes (DEGs) associated with the prognosis of LUSC. PTGIS/HRASLS knockdown and overexpression effects on the LUSC phenotype were analyzed in vitro experiments. Based on the expression distribution of PTGIS/HRASLS, LUSC patients were divided into two clusters by consensus clustering. Clinical information, prognosis, immune infiltration, expression of immune checkpoints, and tumor mutation burden (TMB) level were compared between the TCGA and GSE4573 cohorts. The genes related to clustering and tumor immunity were screened by weighted gene coexpression network analysis (WGCNA), and the target module genes were analyzed by functional enrichment analysis, protein-protein interaction (PPI) analysis, and immune correlation analysis. RESULTS: 191 lipid metabolism-related DEGs were identified, of which 5 genes were independent prognostic genes of LUSC. PTGIS/HRASLS were most closely related to LUSC prognosis and immunity. RT-qPCR, western blot (WB) analysis, and immunohistochemistry (IHC) showed that the expression of PTGIS was low in LUSC, while HRASLS was high. Functionally, PTGIS promoted LUSC proliferation, migration, and invasion, while HRASLS inhibited LUSC proliferation, migration, and invasion. The two clusters' expression and distribution of PTGIS/HRASLS had the opposite trend. Cluster 1 was associated with lower pathological staging (pT, pN, and pTNM stages), better prognosis, stronger immune infiltration, higher expression of immune checkpoints, and higher TMB level than cluster 2. WGCNA found that 28 genes including CD4 and IL10RA were related to the expression of PTGIS/HRASLS and tumor immune infiltration. PTGIS/HRASLS in the GSE4573 cohort had the same effect on LUSC prognosis and tumor immunity as the TCGA cohort. CONCLUSIONS: PTGIS and HRASLS can be used as new therapeutic targets for LUSC as well as biomarkers for prognosis and tumor immunity, which has positive significance for guiding the immunotherapy of LUSC.

摘要

背景：脂质代谢重编程在癌症的发生、发展和免疫调节中起着重要作用。本研究的目的是鉴定和验证与肺鳞状细胞癌（LUSC）表型、预后和免疫特征相关的脂质代谢相关基因（LMRGs）。

方法：在 TCGA 队列中，通过生物信息学和生存分析鉴定与 LUSC 预后相关的脂质代谢差异表达基因（DEGs）。在体外实验中分析 PTGIS/HRASLS 敲低和过表达对 LUSC 表型的影响。基于 PTGIS/HRASLS 的表达分布，通过共识聚类将 LUSC 患者分为两个聚类。比较 TCGA 和 GSE4573 队列的临床信息、预后、免疫浸润、免疫检查点表达和肿瘤突变负担（TMB）水平。通过加权基因共表达网络分析（WGCNA）筛选与聚类和肿瘤免疫相关的基因，并通过功能富集分析、蛋白质-蛋白质相互作用（PPI）分析和免疫相关性分析分析靶模块基因。

结果：鉴定出 191 个与脂质代谢相关的 DEGs，其中 5 个基因是 LUSC 的独立预后基因。PTGIS/HRASLS 与 LUSC 预后和免疫最密切相关。RT-qPCR、western blot（WB）分析和免疫组化（IHC）显示，LUSC 中 PTGIS 的表达较低，而 HRASLS 的表达较高。功能上，PTGIS 促进 LUSC 的增殖、迁移和侵袭，而 HRASLS 抑制 LUSC 的增殖、迁移和侵袭。两个聚类的 PTGIS/HRASLS 表达和分布呈相反趋势。与聚类 2 相比，聚类 1 与较低的病理分期（pT、pN 和 pTNM 分期）、较好的预后、更强的免疫浸润、更高的免疫检查点表达和更高的 TMB 水平相关。WGCNA 发现包括 CD4 和 IL10RA 在内的 28 个基因与 PTGIS/HRASLS 的表达和肿瘤免疫浸润相关。在 GSE4573 队列中，PTGIS/HRASLS 对 LUSC 预后和肿瘤免疫的影响与 TCGA 队列相同。

结论：PTGIS 和 HRASLS 可作为 LUSC 的新治疗靶点和预后及肿瘤免疫标志物，对指导 LUSC 的免疫治疗具有积极意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82ec/9873467/5d1ea2692c6f/OMCL2023-6811625.013.jpg
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