直肠癌新辅助治疗中放射性肠损伤相关基因生物信息学分析

Bioinformatics analysis of genes related to radiation-induced intestinal injury in neoadjuvant therapy for rectal cancer

目的探究直肠正常组织放射性损伤相关基因并讨论其潜在的作用机制。方法利用基因表达数据库(gene expression omnibus,GEO)的GSE15781中直肠癌旁正常组织样本表达谱芯片组,通过limma包比较正常直肠组织在放疗前后的差异基因,接着对差异基因进行功能富集分析和构建蛋白相互作用网络发现放射性损伤相关的作用机制。结果筛选出正常直肠组织在放疗前后的122个差异基因,其中上调基因86个,下调基因36个。基因本体(gene ontology,GO)富集分析显示差异基因参与改变直肠组织对类固醇激素、糖皮质激素、皮质类固醇反应,多种免疫细胞(单核细胞、髓样细胞、白细胞)趋化和迁移等生物学行为变化;影响DNA结合转录激活因子活性、氧化还原酶活性和受体配体活性等分子功能。京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)通路富集分析显示差异基因介导TNF信号通路等,与直肠放射性损伤存在一定相关性。蛋白相互作用网络则提示IL6、FOS、JUN、CCL2、PTGS2等基因在直肠放射性损失中发挥关键作用。结论本研究发现直肠癌旁正常组织放疗后IL6、FOS、JUN、CCL2等基因失调,从而改变直肠黏膜炎症及免疫细胞浸润并介导TNF信号通路,从而在直肠放射性损伤中发挥重要作用。

Objective To explore the genes related to radiation damage in normal rectal tissues and discover its potential mechanism of action.Methods The gene expression spectrum chip of GSE15781 in the Gene Expression Omnibus(GEO)database was used,and the differential gene expressions of normal rectal tissue before and after radiotherapy were compared by limma package,followed by functional enrichment analysis of differential genes and construction of protein interaction network so as to discover the mechanism of action of radiation damage.Results We screened 122 differential genes in normal rectal tissues before and after radiotherapy,including 86 up-regulated genes and 36 down-regulated genes.Gene ontology enrichment analysis showed that differential genes were involved in changing rectal tissue response to steroid hormones,glucocorticoids,corticosteroids as well as chemotactic migration of various immune cells(monocytes,myeloid cells,leukocytes),and affecting molecular functions such as DNA-binding transcriptional activator activity,oxidoreductase activity,and receptor ligand activity.KEGG(Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis showed that differential gene mediated TNFsignaling pathway and had a certain correlation with rectal radiation injury. Protein interactionnetworks suggest that genes such as IL6, FOS, JUN, CCL2, and PTGS2 play key roles in rectalradioactivity loss. Conclusions This study reveals that IL6, FOS, JUN, CCL2 gene imbalance innormal tissues adjacent to rectal cancer after radiotherapy can alter rectal mucosal inflammation andimmune cell infiltration and mediate TNF signaling pathway. Thus, it plays an important role in therectal radiation injury.