N6-甲基腺苷修饰与非小细胞肺癌淋巴结转移相关  

Correlation between N6-methyladenosine modification and lymph node metastasis in non-small cell lung cancer

作　　者：董博 吴春莉 黄岚[2] 李世浩 张春敭[1] 吴彬[1] 盛银良 刘亚飞[1] 叶贯超 齐宇 Dong Bo;Wu Chunli;Huang Lan;Li Shihao;Zhang Chunyang;Wu Bin;Sheng Yinliang;Liu Yafei;Ye Guanchao;Qi Yu(Department of Thoracic Surgery,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China;Biotherapy Center,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China)

机构地区：[1]郑州大学第一附属医院胸外科,450052 [2]郑州大学第一附属医院生物治疗中心,450052

出　　处：《中华实验外科杂志》2021年第8期1423-1426,共4页Chinese Journal of Experimental Surgery

基　　金：白求恩公益基金会医学科学研究基金(KX009AN)。

摘　　要：目的探讨N6-甲基腺苷(m6A)修饰与非小细胞肺癌(NSCLC)淋巴结转移的相关性。方法从癌症基因组图谱(TCGA)数据库下载NSCLC患者的转录组测序数据,共包含1037例原发肺癌组织样本和108例癌旁组织样本。分析参与m6A修饰过程的调控蛋白在肿瘤组织和癌旁正常组织样本中表达水平的差异,利用加权基因共表达分析(WGCNA)算法识别与m6A调控因子存在共表达关系的信使RNA(mRNA)和非编码RNA(ncRNA)并根据RNA的表达模式对NSCLC患者进行共识聚类。采用t检验比较聚类亚组间m6A甲基化丰度的差异,采用χ2检验比较组间淋巴结转移发生率的差异。结果共纳入20个m6A调控因子,肿瘤组织中15个调控因子的表达水平显著上调[甲基转移酶样蛋白3(METTL3)、YTH结构域蛋白1(YTHDC1)、YTH结构域结合蛋白1-3(YTHDF1-3)、异质核核糖蛋白A2B1(HNRNPA2B1)和HNRNPC、ALK B同源物5(ALKBH5)等],3个调控因子显著下调[M0ETTL14、含锌指CCCH结构域蛋白13(Zc3h13)、脂肪和肥胖相关蛋白(FTO)],差异有统计学意义(P<0.05),YTHDC2和METTL16差异无统计学意义。通过WGCNA算法识别出454个与调控因子存在共表达关系的mRNAs和400个ncRNAs[325个长链非编码RNAs(lncRNAs)、23个微小RNAs(miRNAs)、28个核仁小RNAs(snoRNAs)、24个核内小RNAs(snRNAs)]。根据854个RNAs的表达模式进行共识聚类,将NSCLC患者分为2个聚类亚组(聚类1和聚类2)。WT1相关蛋白WTAP(t=14.322,P<0.01)和HNRNPC(t=15.424,P<0.01)等11个调控因子的表达水平在聚类1中均显著上调,其他9个调节因子在聚类亚组间差异无统计学意义,聚类1患者具有较高的m6A甲基化丰度。聚类1患者淋巴结转移发生率38.16%(292/765)明显高于聚类2组的22.27%(55/247),差异有统计学意义(χ^(2)=19.487,P<0.01)。结论通过m6A甲基化与非小细胞肺癌淋巴结转移的相关分析,有助于探讨肺癌淋巴结转移相关机制。Objective To investigate the correlation between N6-methyladenosine(m6A)modification and lymph node metastasis in non-small cell lung cancer(NSCLC).Methods The transcriptome sequencing data of NSCLC patients was downloaded from The Cancer Genome Atlas(TCGA)database.A total of 1037 primary lung cancer samples and 108 para-cancerous tissue samples were extracted.Firstly,the expression levels of m6A regulators were analyzed in tumor tissues versus adjacent tissues.Subsequently,the Weighted Gene Co-expression Network Analysis(WGCNA)algorithm was used to identify mRNA and non-coding RNA(ncRNA)that were co-expressed with m6A regulators.Finally,consensus clustering was performed for NSCLC patients according to the RNAs expression patterns.The t test was used to compare the expression levels of m6A regulators among the cluster subgroups,and the chi-square test was used to compare the differences in the incidence of lymph node metastasis.Results A total of 20 m6A regulators were included.The expression levels of 15 regulators in tumor tissues were significantly up-regulated[methyltransferase 3(METTL3),YTH domain containing 1(YTHDC1),YTH domain RNA binding protein 1-3(YTHDF1-3),heterogeneous nuclear Riboprotein A2B1(HNRNPA2B1)and HNRNPC,ALK B homolog 5(ALKBH5),etc.],3 regulators were significantly down-regulated[METTL14,zinc finger CCCH-type containing 13(Zc3h13),fat and obesity related Protein(FTO)],and the differences were statistically significant(P<0.05).There was no significant difference in the expression levels of YTHDC2 and METTL16 between the two groups.A total of 454 mRNAs and 400 ncRNAs[325 long non-coding RNAs(lncRNAs)],23 microRNAs(miRNAs),28 small nucleolar RNAs(snoRNAs),24 small nuclear RNAs(snRNAs) were identified using the WGCNA algorithm.According to the expression patterns of 854 RNAs,NSCLC patients were clustered into 2 subgroups(cluster 1 and cluster 2).The expression levels of 11 regulators,such as WT1-related protein(WTAP)(t=14.322,P<0.01)and HNRNPC(t=15.424,P<0.01),were significantly up-regulated in

关 键 词：肺癌 甲基化 淋巴结转移 

分 类 号：R734.2[医药卫生—肿瘤]