趋化因子配体9对乳腺癌脑转移全脑放射治疗患者认知功能衰退的影响

Effect of chemokine CXC ligand 9 on cognitive function impairment in breast cancer patients with brain metastases receiving whole-brain radiotherapy

目的基于生物信息学方法探讨趋化因子配体9(CXCL9)对乳腺癌脑转移全脑放射治疗患者认知功能衰退的影响。方法筛选和下载GEO数据库中乳腺癌脑转移数据集GSE43837和GSE12276及阿尔茨海默病(AD)数据集GSE161199的mRNA,采用limma法和韦恩图筛选共同差异表达基因(DEGs),通过GeneMANIA网站进行蛋白互作和功能预测。选取2021年1月-2023年1月于河北北方学院附属第一医院放射治疗科首次就诊的乳腺癌脑转移患者42例,根据认知功能情况分为认知功能正常组与认知功能衰退组,分别于放射治疗前1周和放射治疗后3个月采用酶联免疫吸附法(ELISA)检测血清CXCL9水平,采用简易精神状态检查量表(MMSE)评估患者的认知功能。结果GSE43837和GSE12276数据集的DEGs包括PKP1、POLDIP2、SPAG5、ALDOC、PTPRZ1、PKIA、TLCD1、CPE、PMP22和CXCL9,GSE161199数据集的DEGs包括RPS16、CD79A、LYPD3、RPL28、HBG2、RPL23AP7、TRNR、CXCL9等。韦恩图显示,CXCL9为乳腺癌脑转移与AD的共有DEGs,功能富集分析提示CXCL9参与了细胞对趋化因子的反应、免疫系统进程的负调控、血管形态发生的负调控、Toll样受体信号通路、核苷酸寡聚化结构域(NOD)样受体信号通路和JAK-STAT信号通路等。放射治疗前,认知功能衰退和认知功能正常乳腺癌脑转移患者分别占61.9%、38.1%,MMSE评分差异有统计学意义[(24.53±2.19)分vs.(28.89±1.36)分,P˂0.01]。与认知功能正常组比较,认知功能衰退组患者脑转移瘤数目明显增加,卡氏健康状况量表(KPS)评分、血清CXCL9水平明显降低(P˂0.05)。放射治疗后3个月,认知功能衰退和认知功能正常的乳腺癌脑转移患者分别占47.6%和52.4%,MMSE评分差异有统计学意义[(25.16±1.98)分vs.(28.18±1.08)分,P˂0.01);与认知功能正常组比较,认知功能衰退组患者的血清CXCL9水平明显降低(P=0.003)。与放射治疗前认知功能正常患者比较,放射治疗后认知功能正常的乳腺癌脑转移患者血清CXCL9水平明显降低(P=0.009)。结论认知功能衰退的乳腺癌脑转移患者血清CXCL9水平明显低于认知功能正常的乳腺癌脑转移患者,全脑放射治疗可能与CXCL9水平降低有一定的相关性。

Objective To investigate the effect of chemokine CXC ligand 9(CXCL9)on cognitive function impairment in patients with breast cancer brain metastases undergoing whole-brain radiotherapy(WBRT)using bioinformatics methods.Methods The mRNA of breast cancer brain metastases datasets GSE43837 and GSE12276 and Alzheimer's disease(AD)dataset GSE161199 were screened and downloaded from GEO database.Limma method and Venn diagrams were used to identify common differentially expressed genes(DEGs),and protein-protein interaction and functional prediction through GeneMANIA website assays were performed.A total of 42 patients with breast cancer brain metastases who first visited the Department of Radiotherapy at the First Affiliated Hospital of Hebei North University from January 2021 to January 2023 were selected.Patients were divided into normal cognitive function group and cognitive function impairment group based on cognitive status.Enzyme-linked immunosorbent assay(ELISA)was employed to detect serum CXCL9 levels one week before and three months after radiotherapy.The mini-mental state examination(MMSE)was used to assess patients'cognitive function.Results The DEGs from datasets GSE43837 and GSE12276 included PKP1,POLDIP2,SPAG5,ALDOC,PTPRZ1,PKIA,TLCD1,CPE,PMP22 and CXCL9.The DEGs from GSE161199 included RPS16,CD79A,LYPD3,RPL28,HBG2,RPL23AP7,TRNR,CXCL9.Venn diagram showed that CXCL9 was a common DEG between breast cancer brain metastasis and AD.Functional enrichment analysis indicated that CXCL9 was involved in cellular responses to chemokines,negative regulation of immune system processes,negative regulation of vascular morphogenesis,Toll-like receptor signaling pathway,nucleotide oligomerization domain(NOD)‐like receptor signaling pathway,and JAK-STAT signaling pathway.Before radiotherapy,patients with cognitive function impairment and normal cognitive function accounted for 61.9%and 38.1%,respectively,with a statistically significant difference in MMSE scores[(24.53±2.19)vs.(28.89±1.36),P˂0.01].Compared with normal cognitive function group,patients with cognitive function impairment had a significantly increased number of brain metastases and significantly lower Karnofsky performance status(KPS)scores and serum CXCL9 levels(P˂0.05).Three months after radiotherapy,patients with cognitive function impairment and normal cognitive function accounted for 47.6%and 52.4%,respectively,with a statistically significant difference in MMSE scores[(25.16±1.98)vs.(28.18±1.08),P˂0.01].Compared with normal cognitive function group,patients with cognitive function impairment had significantly lower CXCL9 levels(P=0.003).In patients with normal cognitive function,CXCL9 levels were remarkably lower after radiotherapy compared to those before radiotherapy(P=0.009).Conclusions Patients with cognitive function impairment had significantly lower CXCL9 levels than those with normal cognitive function,and whole-brain radiotherapy may be related to a certain degree of reduction in CXCL9 levels.