通过孟德尔随机化和RNA测序分析探索白细胞介素家族与肺腺癌之间的关系。

Exploring the relationship between the interleukin family and lung adenocarcinoma through Mendelian randomization and RNA sequencing analysis.

作者信息

Zhi Fei-Hang, Liu Wei, Yang Hao-Shuai, Luo Hong-He, Feng Yan-Fen, Lei Yi-Yan

机构信息

Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.

Department of Thoracic Surgery, China-Japan Friendship Hospital, Beijing, China.

出版信息

Discov Oncol. 2024 Sep 12;15(1):436. doi: 10.1007/s12672-024-01325-1.

DOI:10.1007/s12672-024-01325-1

PMID:39264458

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11393260/

Abstract

BACKGROUND

Lung adenocarcinoma (LUAD) is still one of the most prevalent malignancies. Interleukin factors are closely associated with the initiation and progression of cancer. However, the relationship between interleukin factors and LUAD has not been fully elucidated. This study aimed to use Mendelian randomization (MR) and RNA sequencing (RNA-seq) analyses to identify the interleukin factors associated with the onset and progression of LUAD.

METHODS

Exposure-related instrumental variables were selected from interleukin factor summary datasets. The LUAD summary dataset from FINGENE served as the outcome. MR and sensitivity analyses were conducted to screen for interleukin factors associated with LUAD occurrence. Transcriptome analyses revealed the role of interleukin factors in lung tissues. The results were validated through Western blotting and further confirmed with driver gene-negative patients from multiple centers. Potential mechanisms influencing LUAD occurrence and development were explored using bulk RNA-seq and single-cell RNA-seq data.

RESULTS

MR analysis indicated that elevated plasma levels of IL6RB, IL27RA, IL22RA1, and IL16 are causally associated with increased LUAD risk, while IL18R1 and IL11RA exhibit the opposite effect. Transcriptome analyses revealed that IL11RA, IL18R1, and IL16 were downregulated in tumor tissues compared with normal lung tissue, but only higher expression of IL11RA correlated with improved prognosis in patients with LUAD from different centers and persisted even in driver-gene negative patients. The IL11RA protein level was lower in various LUAD cell lines than in human bronchial epithelial cells. The genes co-expressed with IL11RA were enriched in the Ras signaling pathway and glycosylation processes. Fibroblasts were the primary IL11RA-expressing cell population, with IL11RA+fibroblasts exhibiting a more immature state. The genes differentially expressed between IL11RA+and IL11RA- fibroblasts were involved in the PI3K-Akt/TNF signaling pathway.

CONCLUSION

According to the MR and transcriptome analyses, the downregulation of IL11RA was closely related to the occurrence and development of LUAD.

摘要

背景

肺腺癌（LUAD）仍然是最常见的恶性肿瘤之一。白细胞介素因子与癌症的发生和发展密切相关。然而，白细胞介素因子与LUAD之间的关系尚未完全阐明。本研究旨在利用孟德尔随机化（MR）和RNA测序（RNA-seq）分析来确定与LUAD发病和进展相关的白细胞介素因子。

方法

从白细胞介素因子汇总数据集中选择暴露相关的工具变量。来自FINGENE的LUAD汇总数据集作为结果。进行MR和敏感性分析以筛选与LUAD发生相关的白细胞介素因子。转录组分析揭示了白细胞介素因子在肺组织中的作用。通过蛋白质印迹法验证结果，并在多个中心的驱动基因阴性患者中进一步确认。使用批量RNA-seq和单细胞RNA-seq数据探索影响LUAD发生和发展的潜在机制。

结果

MR分析表明，血浆中IL6RB、IL27RA、IL22RA1和IL16水平升高与LUAD风险增加存在因果关系，而IL18R1和IL11RA则表现出相反的作用。转录组分析显示，与正常肺组织相比，肿瘤组织中IL11RA、IL18R1和IL16表达下调，但只有较高的IL11RA表达与不同中心的LUAD患者预后改善相关，甚至在驱动基因阴性患者中也持续存在。各种LUAD细胞系中IL11RA蛋白水平低于人支气管上皮细胞。与IL11RA共表达的基因富集在Ras信号通路和糖基化过程中。成纤维细胞是主要表达IL11RA的细胞群体，IL11RA+成纤维细胞表现出更不成熟的状态。IL11RA+和成纤维细胞之间差异表达的基因参与PI3K-Akt/TNF信号通路。