SHP2靶向抑制对<i>KRAS</i>突变肺癌细胞炎症相关基因表达的影响分析

周文斌; 高玲玲; 陈冀; 曾鹏辉; 张莉; 朱琳琳; 黄晓丹; 颜文青; 陈宇; 张水莲; 郭伟浜; 谢至; 吕志异; 卢丹霞; 张绪超

doi:10.12019/j.issn.1671-5144.2023.04.007

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

摘要

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。

Abstract:
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.

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