青蒿琥酯及CXCR4通路对肺腺癌的影响

Effects of Artesunate and CXCR4 Pathway on Lung Adenocarcinoma

目的探讨趋化因子受体4(CXCR4)对肺腺癌患者预后的影响及青蒿琥酯对肺腺癌CXCR4通路的作用。方法下载TCGA数据库中肺腺癌患者的RNA表达谱及临床数据,比较不同肿瘤分期患者的CXCR4表达水平,并分为高表达组和低表达组,各246例。比较两组患者的生存时间;将患者各RNA表达水平逐一与CXCR4表达水平进行Pearson相关性检测,根据相关系数选取相关性最高的50个基因。采用不同浓度青蒿琥酯干预肺腺癌H1975细胞24 h后,CCK-8法检测细胞的增殖能力,RT-qPCR检测CXCR4和细胞黏附素1相互作用蛋白(CYTIP)的mRNA表达水平。结果CXCR4高表达组患者中位生存时间显著长于低表达组(P<0.05);根据病理分期分组,Ⅳ期患者的CXCR4表达水平显著低于Ⅰ-Ⅲ期(P<0.05);根据T分期分组,T2期和T4期患者的CXCR4表达水平显著低于T1期(P<0.05),T4期患者的CXCR4表达水平均显著低于其他三期(P<0.05);在检测的19989个基因中,有9694个与CXCR4存在相关性(P<0.05),其中CYTIP的相关性最高。细胞实验结果显示,青蒿琥酯对肺腺癌H1975细胞株的增殖有明显抑制作用,并呈浓度依赖性;青蒿琥酯可抑制CXCR4基因的表达(P<0.05)。结论CXCR4低表达与肺腺癌患者远期生存率降低及肿瘤分期较高有关;青蒿琥酯可抑制肺腺癌H1975细胞增殖,其机制可能与下调CXCR4的表达有关。

Objective To investigate the effect of chemokine receptor 4(CXCR4)on the prognosis of patients with lung adenocarcinoma and the effect of artesunate on CXCR4 pathway in lung adenocarcinoma.Methods The RNA expression profile and clinical data of patients with lung adenocarcinoma in TCGA database were downloaded,and the expression levels of CXCR4 in patients with different tumor stages were compared.According to the expression level of CXCR4,the patients were divided into high expression group(n=246)and low expression group(n=246).The survival time of the two groups was compared.The correlation between RNA expression level and CXCR4 expression level was detected one by one,and 50 genes with the highest correlation were selected according to the correlation coefficient.After treated with different concentrations of artesunate for 24 hours,the proliferation of H1975 cells was detected by CCK-8 assay,and the mRNA expression of CXCR4 and adhesin 1 interacting protein(CYTIP)was detected by RT-qPCR.Results The median survival time of CXCR4 high expression group was longer than that of CXCR4 low expression group,and the difference was statistically significant(P<0.05).For pathological stage,the expression level of CXCR4 in stage Ⅳ patients was significantly lower than that in stage Ⅰ-Ⅲ patients(P<0.05).For T stage,the expression level of CXCR4 in patients of stage T2 and T4 was significantly lower than that in patients with stage T1,and the expression level in patients of stage T4 was lower than that in patients of the other three stages.Of the 19989 genes detected,9694 genes were associated with CXCR4,among which CYTIP was the highest.Artesunate inhibited the proliferation of H1975 cell line in a concentration-dependent manner,and it also inhibited the expression of CXCR4 genes(P<0.05).Conclusion The low expression of CXCR4 is related to the decrease of long-term survival rate and the higher tumor grade.Artesunate could inhibit the proliferation of lung adenocarcinoma H1975 cells, and its mechanism may be related to the down-regulation of CXCR4 expression.