钠/氢交换调节因子1是结直肠腺癌临床预后的预测因子
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摘要
目的寻找与结直肠腺癌侵袭和迁移相关的因子。方法收集TCGA及GEO数据库中结直肠腺癌相关数据进行SAM差异表达基因分析;将得到的差异基因通过DAVID进行聚类分析;寻找与侵袭迁移相关的基因;并对TCGA数据库中的患者临床信息进行回顾性分析及生存预后分析;同时收集50例具有详细临床及预后信息的结直肠腺癌组织及配对癌旁组织进行免疫组织化学染色来验证上述结果,并绘制ROC线进行评估。结果 DAVID聚类分析发现6个与迁移相关的基因集(P<0.05),其中下调的基因有DLC1、EPB41L3、KIT、PARVA、SLC9A3R1和TPM1。而SLC9A3R1编码的钠/氢交换调节因子1(NHERF1),是一种能与细胞骨架及多种信号蛋白相互作用的多功能连接蛋白。TCGA数据分析显示,结直肠腺癌中NHERF1的mRNA水平较正常结直肠组织降低。独立临床队列数据的免疫组化结果显示,在高级别及发生淋巴结转移的组织中NHERF1表达降低。结论 NHERF1表达降低是影响结直肠腺癌患者生存期的一个独立影响因子,可能与其促进肿瘤转移有关。NHERF1表达降低是一个潜在的诊断和预测结直肠腺癌不良预后的指标。
Objective To find factors related to colorectal adenocarcinoma invasion and migration. Methods The data of colorectal adenocarcinoma in TCGA and GEO databases were collected for SAM differential analysis. The differentially expressed genes were collected through DAVID, and genes related to invasion and migration were identified. In addition, cancer and paired adjacent tissues from 50 cases of Chinese colorectal adenocarcinoma patients with detailed clinical and prognostic information were collected for immunohistochemical staining to verify the above results. The ROC curve was drawn to evaluate the ability of this gene or its encoded protein for colorectal adenocarcinoma diagnosis. Results Totally 6 clusters of migration-related genes were found by DAVID analysis(P<0.05). The down-regulated genes were DLC1, EPB41L3, KIT, PARVA, SLC9A3R1 and TPM1. NHERF1, encoded by SLC9A3R1, was a scaffold protein that interacts with cytoskeleton and various signaling proteins. Data showed that both mRNA and protein levels of NHERF 1 in colorectal adenocarcinoma were lower than those in normal tissue, and its expression was decreased in high-grade and lymph node metastasis. Conclusions The decreased expression of NHERF1 is an independent factor associated with poorer survival of colorectal adenocarcinoma patients, which may result from its metastasis. Decreased expression of NHERF1 is a potential indicator for prediction of colorectal adenocarcinoma prognosis.
Objective To find factors related to colorectal adenocarcinoma invasion and migration. Methods The data of colorectal adenocarcinoma in TCGA and GEO databases were collected for SAM differential analysis. The differentially expressed genes were collected through DAVID, and genes related to invasion and migration were identified. In addition, cancer and paired adjacent tissues from 50 cases of Chinese colorectal adenocarcinoma patients with detailed clinical and prognostic information were collected for immunohistochemical staining to verify the above results. The ROC curve was drawn to evaluate the ability of this gene or its encoded protein for colorectal adenocarcinoma diagnosis. Results Totally 6 clusters of migration-related genes were found by DAVID analysis(P<0.05). The down-regulated genes were DLC1, EPB41L3, KIT, PARVA, SLC9A3R1 and TPM1. NHERF1, encoded by SLC9A3R1, was a scaffold protein that interacts with cytoskeleton and various signaling proteins. Data showed that both mRNA and protein levels of NHERF 1 in colorectal adenocarcinoma were lower than those in normal tissue, and its expression was decreased in high-grade and lymph node metastasis. Conclusions The decreased expression of NHERF1 is an independent factor associated with poorer survival of colorectal adenocarcinoma patients, which may result from its metastasis. Decreased expression of NHERF1 is a potential indicator for prediction of colorectal adenocarcinoma prognosis.
引文
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[10] Hayashi Y,Molina JR,Hamilton SR,et al.NHERF1/EBP50 is a new marker in colorectal cancer[J].Neoplasia,2010,12:1013-1022.
[11] Guo Y,Wang M,Jia X,et al.Wnt signaling pathway upregulates DNMT1 to trigger NHERF1 promoter hypermethylation in colon cancer[J].Oncol Rep,2018,40:1165-1173.
[12] Vaquero J,Nguyen HT,Claperon A,et al.Role of the PDZ-scaffold protein NHERF1/EBP50 in cancer biology:from signaling regulation to clinical relevance[J].Oncogene,2017,36:3067-3079.
[2] Schmoll HJ,Van Cutsem E,Stein A,et al.ESMO Consensus Guidelines for management of patients with colon and rectal cancer.a personalized approach to clinical decision making[J].Ann Oncol,2012,23:2479-2516.
[3] 朱攀,雷蜜,高波.肿瘤标志物及血管新生因子与结直肠癌患者临床分期及肿瘤转移相关[J].基础医学与临床,2019,39:59-62.
[4] 张鑫东,葛晓蕾,刘省存,等.血清CA199和CEA对结直肠癌转移和预后预测的价值[J].中华疾病控制杂志,2018,22:57-61.
[5] Wang Q,Qin Q,Song R,et al.NHERF1 inhibits beta-catenin-mediated proliferation of cervical cancer cells through suppression of alpha-actinin-4 expression[J].Cell Death Dis,2018,9:668.doi:10.1038/S41419-018-0711-x.
[6] Dai JL,Wang L,Sahin AA,et al.NHERF (Na+/H+ exchanger regulatory factor) gene mutations in human breast cancer[J].Oncogene,2004,23:8681-8687.
[7] Ediger TR,Kraus WL,Weinman EJ,et al.Estrogen receptor regulation of the Na+/H+ exchange regulatory factor[J].Endocrinology,1999,140:2976-2982.
[8] Stemmer-Rachamimov AO,Wiederhold T,Nielsen GP,et al.NHE-RF,a merlin-interacting protein,is primarily expressed in luminal epithelia,proliferative endometrium,and estrogen receptor-positive breast carcinomas[J].Am J Pathol,2001,158:57-62.
[9] Georgescu MM,Cote G,Agarwal NK,et al.NHERF1/EBP50 controls morphogenesis of 3D colonic glands by stabilizing PTEN and ezrin-radixin-moesin proteins at the apical membrane[J].Neoplasia,2014,16:365-374.
[10] Hayashi Y,Molina JR,Hamilton SR,et al.NHERF1/EBP50 is a new marker in colorectal cancer[J].Neoplasia,2010,12:1013-1022.
[11] Guo Y,Wang M,Jia X,et al.Wnt signaling pathway upregulates DNMT1 to trigger NHERF1 promoter hypermethylation in colon cancer[J].Oncol Rep,2018,40:1165-1173.
[12] Vaquero J,Nguyen HT,Claperon A,et al.Role of the PDZ-scaffold protein NHERF1/EBP50 in cancer biology:from signaling regulation to clinical relevance[J].Oncogene,2017,36:3067-3079.
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