Wang Jin, Chen Tao, Yu Xiaofan, OUYang Nan, Tan Lirong, Jia Beibei, Tong Jian, Li Jianxiang
Department of Toxicology, School of Public Health, Medical College of Soochow University, Renai Road, Suzhou, 215123, China.
Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Renai Road, Suzhou, 215123, China.
J Transl Med. 2020 Aug 14;18(1):313. doi: 10.1186/s12967-020-02474-x.
Lung cancer is one of the most common carcinomas in the world, and lung adenocarcinoma (LUAD) is the most lethal and most common subtype of lung cancer. Cigarette smoking is the most leading risk factor of lung cancer, but it is still unclear how normal lung cells become cancerous in cigarette smokers. This study aims to identify potential smoking-related biomarkers associated with the progression and prognosis of LUAD, as well as their regulation mechanism using an in vitro carcinogenesis model and bioinformatics analysis.
Based on the integration analysis of four Gene Expression Omnibus (GEO) datasets and our mRNA sequencing analysis, 2 up-regulated and 11 down-regulated genes were identified in both S30 cells and LUAD. By analyzing the LUAD dataset in The Cancer Gene Analysis (TCGA) database, 3 of the 13 genes, viz., glycophorin C (GYPC), NME/NM23 nucleoside diphosphate kinase 1 (NME1) and slit guidance ligand 2 (SLIT2), were found to be significantly correlated with LUAD patients' smoking history. The expression levels of GYPC, NME1 and SLIT2 in S30 cells and lung cancer cell lines were validated by quantitative PCR, immunofluorescence, and western blot assays. Besides, these three genes are associated with tumor invasion depth, and elevated expression of NME1 was correlated with lymph node metastasis. The enrichment analysis suggested that these genes were highly correlated to tumorigenesis and metastasis-related biological processes and pathways. Moreover, the increased expression levels of GYPC and SLIT2, as well as decreased expression of NME1 were associated with a favorable prognosis in LUAD patients. Furthermore, based on the multi-omics data in the TCGA database, these genes were found to be regulated by DNA methylation.
In conclusion, our observations indicated that the differential expression of GYPC, NME1 and SLIT2 may be regulated by DNA methylation, and they are associated with cigarette smoke-induced LUAD, as well as serve as prognostic factors in LUAD patients.
肺癌是世界上最常见的癌症之一，肺腺癌（LUAD）是肺癌中最致命且最常见的亚型。吸烟是肺癌最主要的危险因素，但目前仍不清楚吸烟者的正常肺细胞是如何癌变的。本研究旨在利用体外致癌模型和生物信息学分析，鉴定与LUAD进展和预后相关的潜在吸烟相关生物标志物及其调控机制。
基于对四个基因表达综合数据库（GEO）数据集的整合分析以及我们的mRNA测序分析，在S30细胞和LUAD中均鉴定出2个上调基因和11个下调基因。通过分析癌症基因分析（TCGA）数据库中的LUAD数据集，发现这13个基因中的3个，即血型糖蛋白C（GYPC）、NME/NM23核苷二磷酸激酶1（NME1）和缝隙引导配体2（SLIT2），与LUAD患者的吸烟史显著相关。通过定量PCR、免疫荧光和蛋白质印迹分析验证了S30细胞和肺癌细胞系中GYPC、NME1和SLIT2的表达水平。此外，这三个基因与肿瘤浸润深度相关，NME1表达升高与淋巴结转移相关。富集分析表明，这些基因与肿瘤发生和转移相关的生物学过程及通路高度相关。此外，GYPC和SLIT2表达水平升高以及NME1表达降低与LUAD患者的良好预后相关。此外，基于TCGA数据库中的多组学数据，发现这些基因受DNA甲基化调控。
总之，我们的观察结果表明，GYPC、NME1和SLIT2的差异表达可能受DNA甲基化调控，它们与吸烟诱导的LUAD相关，并且可作为LUAD患者的预后因素。
Zotero 插件
