TMEFF2 Deregulation Contributes to Gastric Carcinogenesis and Indicates Poor Survival Outcome
TMEFF2 Deregulation Contributes to Gastric Carcinogenesis and Indicates Poor Survival Outcome
复制标题
TMEFF2 放松管制会导致胃癌发生并表明生存结果不佳
DOI：
10.1158/1078-0432.ccr-14-0315
复制
发表时间：
2014-09-01
影响因子：
11.5
通讯作者：
Fang, Jing-Yuan
中科院分区：
文献类型：
--
作者：
Sun, Tiantian;Du, Wan;Fang, Jing-Yuan
目的：具有EGF和两个卵泡抑素基序2 （TMEFF2）的跨膜蛋白在胃癌中的作用及其临床意义尚不清楚。实验设计：进行基因表达谱分析，并利用基因集富集分析（GSEA）探索其基因特征。用TMEFF2或对照质粒转染AGS和MKN45细胞，分析其基因表达模式、增殖和凋亡情况。用shrna敲低TMEFF2的表达，并评估对基因组稳定性的影响。TMEFF2和SHP-1的相互作用通过质谱法和免疫沉淀法测定。结果：综合分析发现，TMEFF2在胃癌病例中的表达明显降低，且其表达与病理分期差、肿瘤大小大、预后差呈负相关。肿瘤基因组图谱（TCGA）和吉林数据库的GSEA显示，TMEFF2低表达患者的细胞增殖、凋亡和DNA损伤相关基因富集。TMEFF2功能的获得通过增加胃癌细胞凋亡和阻断细胞周期来抑制细胞增殖。蛋白酪氨酸磷酸酶SHP-1被确定为TMEFF2的结合伙伴和TMEFF2功能的中介。TMEFF2表达与SHP-1呈正相关，TMEFF2和SHP-1水平均较高的胃癌患者预后较好。结论：TMEFF2通过与SHP-1的直接相互作用在胃癌中发挥抑瘤作用，可能是潜在的癌变生物标志物。临床癌症研究；20 (17);4689 - 704。AACR©2014。
Purpose: The role and clinical implication of the transmembrane protein with EGF and two follistatin motifs 2 (TMEFF2) in gastric cancer is poorly understood. Experimental Design: Gene expression profile analyses were performed and Gene Set Enrichment Analysis (GSEA) was used to explore its gene signatures. AGS and MKN45 cells were transfected with TMEFF2 or control plasmids and analyzed for gene expression patterns, proliferation, and apoptosis. TMEFF2 expression was knocked down with shRNAs, and the effects on genome stability were assessed. Interactions between TMEFF2 and SHP-1 were determined by mass spectrometry and immunoprecipitation assays. Results: Integrated analysis revealed that TMEFF2 expression was significantly decreased in gastric cancer cases and its expression was negatively correlated with the poor pathologic stage, large tumor size, and poor prognosis. GSEA in The Cancer Genome Atlas (TCGA) and Jilin datasets revealed that cell proliferation, apoptosis, and DNA damage–related genes were enriched in TMEFF2 lower expression patients. Gain of TMEFF2 function decreased cell proliferation by increasing of apoptosis and blocking of cell cycle in gastric cancer cells. The protein tyrosine phosphatase SHP-1 was identified as a binding partner of TMEEF2 and mediator of TMEFF2 function. TMEFF2 expression positively correlated with SHP-1, and a favorable prognosis was more likely in patients with gastric cancer with higher levels of both TMEFF2 and SHP-1. Conclusion: TMEFF2 acts as a tumor suppressor in gastric cancer through direct interaction with SHP-1 and can be a potential biomarker of carcinogenesis. Clin Cancer Res; 20(17); 4689–704. ©2014 AACR.