SHP2靶向抑制对KRAS突变肺癌细胞炎症相关基因表达的影响分析  

Impact of SHP2 Targeted Inhibition on the Expression of Inflammation-Related Genes in KRAS-Mutant Lung Cancer Cells

作　　者：周文斌 高玲玲 陈冀 曾鹏辉 张莉[2,3] 朱琳琳 黄晓丹[1,2] 颜文青 陈宇 张水莲[2] 郭伟浜 谢至[2] 吕志异 卢丹霞 张绪超 ZHOU Wen-bin;GAO Ling-ling;CHEN Ji;ZENG Peng-hui;ZHANG Li;ZHU Lin-lin;HUANG Xiao-dan;YAN Wen-qing;CHEN Yu;ZHANG Shui-lian;GUO Wei-bang;XIE Zhi;LV Zhi-yi;LU Dan-xia;ZHANG Xu-chao(School of Medicine,South China University of Technology,Guangzhou 510006,China;Guangdong Lung Cancer Institute,Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences),Southern Medical University,Guangzhou 510080,China;The Second School of Clinical Medicine,Southern Medical University,Guangzhou 510515,China)

机构地区：[1]华南理工大学医学院,广州510006 [2]广东省肺癌研究所,南方医科大学附属广东省人民医院(广东省医学科学院),广州510080 [3]南方医科大学第二临床医学院,广州510515

出　　处：《循证医学》2023年第4期236-243,共8页The Journal of Evidence-Based Medicine

基　　金：国家自然科学基金面上项目(82173202,XZ)。

摘　　要：目的 探究Src同源2结构域蛋白酪氨酸磷酸酶(Src homology region 2-containing protein tyrosine phosphatase 2,SHP2)抑制剂对KRAS突变肺癌细胞中炎症相关基因表达的调节作用,旨在为KRAS突变肺癌治疗的个体化和精准化提供依据。方法 使用SHP2抑制剂SHP099处理5株KRAS突变的人肺癌细胞系,western blot分析ERK1/2等信号通路蛋白活化水平。采用RNA测序分析药物或DMSO作用后配对样本基因表达情况,对差异表达基因进行基因本体(Gene Ontology,GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集分析揭示功能通路富集情况。采用RT-qPCR验证差异基因相对表达水平。结果 SHP2抑制剂处理后,KRAS突变肺癌细胞中的p-SHP2和p-ERK1/2表达水平显著下调。转录组测序和差异基因分析显示,SHP2靶向抑制改变了多个信号通路基因的表达,特别是白细胞介素17(interleukin 17,IL-17)通路相关的CXCL1、CXCL2、CXCL8、MMP1、PTGS2等炎症相关基因表达受到显著下调。结论 SHP2靶向抑制可影响KRAS突变肺癌细胞的IL-17信号通路炎症相关基因表达情况,为进一步阐述靶向SHP2调节肺癌免疫微环境提供了初步证据。Objective This study aims to investigate the impact of Src homology region 2-containing protein tyrosine phosphatase 2(SHP2)inhibitor on the expression of inflammation-related genes in KRAS-mutant lung cancer cells,providing a foundational basis for personalized and precision therapies targeting KRAS-mutant lung cancer in the future.Methods Five KRAS-mutant human lung cancer cell lines were treated with the SHP2 inhibitor SHP099.Western blot was conducted to assess the activation levels of ERK1/2 and other signaling pathway proteins.RNA sequencing was used to analyze the gene expression profiles of paired samples after SHP099/DMSO treatment.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were used to reveal the enriched functional pathways of differentially expressed genes.Furthermore,RT-qPCR was employed to validate the relative expression levels of these genes.Results Treatment with the SHP2 inhibitor resulted in a significant downregulation of p-SHP2 and p-ERK1/2 in KRAS-mutant lung cancer cells.Transcriptome sequencing and differential gene analysis demonstrated that the use of SHP2 inhibitor affected the expression of numerous genes,particularly downregulating inflammation-related genes such as CXCL1,CXCL2,CXCL8,MMP1,and PTGS2,which were associated with the interleukin 17(IL-17)pathway.Conclusions SHP2 targeted inhibition significantly affects the expression of inflammation-related genes within the IL-17 signaling pathway in KRAS-mutant lung cancer cells,providing preliminary evidence for further exploring the potential of targeting SHP2 to regulate the immune microenvironment in lung cancer.

关 键 词：KRAS突变非小细胞肺癌 SHP2 IL-17通路 炎症 

分 类 号：R734.2[医药卫生—肿瘤]