蛋白激酶AURKA介导的大肠癌肿瘤微环境特征及中药有效成分挖掘  

Characteristics of Aurora Kinase A-Mediated Tumor Microenvironment in Colorectal Cancer and Mining of Active Compounds From Chinese Herbs

作　　者：李梦瑶 花东明 王志燕 刘芝亦 龚航军[2] 孙云川[3] 呼雪庆 王炎[1] LI Mengyao;HUA Dongming;WANG Zhiyan;LIU Zhiyi;GONG Hangjun;SUN Yunchuan;HU Xueqing;WANG Yan(Department of Medical Oncology,Shuguang Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Department of Gastroenterology,Shuguang Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Department of Medical Oncology,Cangzhou Hospital of Integrated Traditional and Western Medicine,Cangzhou 061000,China)

机构地区：[1]上海中医药大学附属曙光医院肿瘤科,上海201203 [2]上海中医药大学附属曙光医院胃肠外科,上海201203 [3]河北省沧州中西医结合医院肿瘤科,沧州061000

出　　处：《四川大学学报(医学版)》2025年第1期59-67,共9页Journal of Sichuan University(Medical Sciences)

基　　金：国家自然科学基金资助项目(No.82122075);上海市白玉兰人才浦江项目(No.23PJ1412400);上海市炎癌转化病证生物学前沿研究基地(No.2021KJ03-12)资助。

摘　　要：目的探讨蛋白激酶Aurora kinase A(AURKA)对大肠癌肿瘤微环境的影响,并预测作用于AURKA的中药成分。方法基于TCGA数据库中380例大肠癌组织和51例癌旁组织的转录组学数据及其临床信息,采用xCell方法分析肿瘤组织中不同细胞的浸润程度,通过分子对接预测可结合AURKA的中药有效成分。结果AURKA在大肠癌肿瘤组织中表达高于癌旁组织(P<0.05),且其高表达的大肠癌患者总生存期较短。与AURKA低表达组相比,AURKA高表达组的巨噬细胞、单核细胞、效应记忆CD4+和CD8+T细胞等杀伤性免疫细胞的丰度下调(P<0.05);此外,T细胞毒性作用降低(P<0.05)。进一步分析发现,AURKA表达与髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)丰度及其趋化因子CXCL2和CXCL5表达呈正相关(P<0.05)。AURKA高表达组与低表达组的差异基因主要富集于单核细胞迁移、趋化因子引起的细胞反应等生物过程。中药成分橙皮苷(hesperidin)、马兜铃酸AⅡa(aristololactam AⅡa)、阿魏酸(anacardic acid)、香豆雌酚(coumestrol)、17β-雌二醇(17β-estradiol)等与AURKA的结合能均小于-1.2 kcal/mol,表明结合具有一定的稳定性,其中17β-雌二醇与AURKA-3UOL的结合稳定性最好。结论AURKA在大肠癌组织中的高表达提示其临床预后较差,AURKA可促进大肠癌抑制性免疫微环境的形成,而中药成分17β-雌二醇可能是AURKA的潜在作用药物。Objective To investigate the effects of Aurora kinase A(AURKA)on the tumor microenvironment of colorectal cancer(CRC)and to predict the active compounds in Chinese herbs that can target AURKA.Methods Based on the transcriptomic data and clinical information from 380 CRC tissues and 51 paracancerous tissues in The Cancer Genome Atlas(TCGA)database,the infiltration of different cells in the tumor tissues was analyzed using xCell and the binding of active compounds of Chinese herbs with AURKA was predicted through molecular docking.Results The expression of AURKA was significantly upregulated in CRC tissues compared with that in paracancerous tissues(P<0.05),and CRC patients with high AURKA expression had shorter overall survival.Compared with the AURKA lowexpression group,the abundance of macrophages,monocytes,and effector memory CD4+and CD8+T cells was significantly downregulated in the AURKA high-expression group(P<0.05).In addition,the cytotoxicity of T cells was significantly reduced(P<0.05).Further analysis revealed that AURKA expression was positively correlated with the abundance of myeloid-derived suppressor cells(MDSCs)and the expression levels of their chemokines CXCL2 and CXCL5(P<0.05).Genes that were differentially expressed between the AURKA high-and low-expression groups were mainly enriched in monocyte migration,chemokine-induced cellular responses,and other related processes.Chinese herbal compounds,including hesperidin,aristololactam AⅡa,anacardic acid,coumestrol,and 17β-estradiol,all showed binding energies to AURKA lower than−1.2 kcal/mol,indicating a certain level of binding stability.Among these Chinese herbal compounds,17β-estradiol exhibited the best binding stability to AURKA-3UOL.Conclusion The high expression of AURKA in CRC tissues suggests a poor clinical prognosis.AURKA can promote the development of a suppressive immune microenvironment in CRC,and 17β-estradiol,an active compound from Chinese herbs,is a potential therapeutic agent targeting AURKA.

关 键 词：大肠癌 Aurora kinase A 免疫微环境 中医药 中药成分 

分 类 号：R735.34[医药卫生—肿瘤]