Wang Junyi, Lu Lu, He Xiang, Ma Lijuan, Chen Tao, Li Guoping, Yu Haijie
Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China.
Department of Pulmonary and Critical Care Medicine, Chengdu Institute of Respiratory Health, The Third People's Hospital of Chengdu (The Second Clinical Medical College of Chongqing Medical University in Chengdu), Chengdu 610031, China.
Zhongguo Fei Ai Za Zhi. 2023 Sep 20;26(9):669-683. doi: 10.3779/j.issn.1009-3419.2023.101.25.
Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic, progressive interstitial lung disease with a diagnosed median survival of 3-5 years. IPF is associated with an increased risk of lung cancer. Therefore, exploring the shared pathogenic genes and molecular pathways between IPF and lung adenocarcinoma (LUAD) holds significant importance for the development of novel therapeutic approaches and personalized precision treatment strategies for IPF combined with lung cancer.
Bioinformatics analysis was conducted using publicly available gene expression datasets of IPF and LUAD from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis was employed to identify common genes involved in the progression of both diseases, followed by functional enrichment analysis. Subsequently, additional datasets were used to pinpoint the core shared genes between the two diseases. The relationship between core shared genes and prognosis, as well as their expression patterns, clinical relevance, genetic characteristics, and immune-related functions in LUAD, were analyzed using The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing datasets. Finally, potential therapeutic drugs related to the identified genes were screened through drug databases.
A total of 529 shared genes between IPF and LUAD were identified. Among them, SULF1 emerged as a core shared gene associated with poor prognosis. It exhibited significantly elevated expression levels in LUAD tissues, concomitant with high mutation rates, genomic heterogeneity, and an immunosuppressive microenvironment. Subsequent single-cell RNA-seq analysis revealed that the high expression of SULF1 primarily originated from tumor-associated fibroblasts. This study further demonstrated an association between SULF1 expression and tumor drug sensitivity, and it identified potential small-molecule drugs targeting SULF1 highly expressed fibroblasts.
This study identified a set of shared molecular pathways and core genes between IPF and LUAD. Notably, SULF1 may serve as a potential immune-related biomarker and therapeutic target for both diseases.
特发性肺纤维化（IPF）是一种特发性慢性进行性间质性肺疾病，确诊后的中位生存期为3至5年。IPF与肺癌风险增加相关。因此，探索IPF与肺腺癌（LUAD）之间共同的致病基因和分子途径，对于开发针对IPF合并肺癌的新型治疗方法和个性化精准治疗策略具有重要意义。
利用基因表达综合数据库（GEO）中公开的IPF和LUAD基因表达数据集进行生物信息学分析。采用加权基因共表达网络分析来识别参与两种疾病进展的共同基因，随后进行功能富集分析。接着，使用其他数据集来确定两种疾病之间的核心共享基因。利用癌症基因组图谱（TCGA）数据库和单细胞RNA测序数据集，分析核心共享基因与预后的关系及其在LUAD中的表达模式、临床相关性、遗传特征和免疫相关功能。最后，通过药物数据库筛选与所鉴定基因相关的潜在治疗药物。
共鉴定出IPF和LUAD之间的529个共享基因。其中，SULF1成为与预后不良相关的核心共享基因。它在LUAD组织中的表达水平显著升高，同时伴有高突变率、基因组异质性和免疫抑制微环境。随后的单细胞RNA测序分析表明，SULF1的高表达主要源于肿瘤相关成纤维细胞。本研究进一步证明了SULF1表达与肿瘤药物敏感性之间的关联，并确定了靶向高表达SULF1成纤维细胞的潜在小分子药物。
本研究确定了IPF和LUAD之间的一组共同分子途径和核心基因。值得注意的是，SULF1可能是这两种疾病潜在的免疫相关生物标志物和治疗靶点。
