LIMD1 is a survival prognostic marker of gastric cancer and hinders tumor progression by suppressing activation of YAP1.
LIMD1 is a survival prognostic marker of gastric cancer and hinders tumor progression by suppressing activation of YAP1.
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LIMD1 是胃癌的生存预后标志物，通过抑制 YAP1 的激活来阻碍肿瘤进展
DOI：
10.2147/cmar.s174856
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发表时间：
2018
影响因子：
3.3
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Zhang D;Li S;Yu W;Chen C;Liu T;Sun Y;Zhao Z;Liu L
本研究旨在探讨LIMD 1在胃癌中的生物学作用及其临床意义。通过Kaplan-Meier Plotter在线工具确定LIMD 1在GC患者中的预后价值。通过体外实验，包括增殖、锚定非依赖性生长、迁移、侵袭和上皮向间质转化（EMT）实验，检测LIMD 1在GC中的生物学功能。Western blot检测LIMD 1调控的下游YAP 1表达水平，免疫荧光染色观察YAP 1在胃癌细胞中的亚定位。使用Oncomine数据库比较GC和正常组织之间LIMD 1的差异表达水平和拷贝数水平。通过cBioPortal描述LIMD 1 mRNA水平和拷贝数水平的相关性。我们还通过Wanderer评估了LIMD 1基因周围的甲基化状态。LIMD 1的表达水平与胃癌患者的预后呈正相关，无论肿瘤分期、大小、淋巴结、转移、Lauren分类、分化、性别、治疗和ERBB 2扩增状态如何。LIMD 1的过表达阻碍了肿瘤的生长、细胞运动、侵袭和转移，而LIMD 1的敲低促进了GC细胞中的这些表型。从机制上讲，YAP 1是LIMD 1的下游效应子之一; LIMD 1抑制YAP 1的表达及其胞内转运。此外，我们发现在一些GC分析数据集中，LIMD 1表达减少。胃癌组织中LIMD 1基因的缺失，而不是DNA甲基化，导致LIMD 1表达的降低。我们的研究结果确定LIMD 1作为一个令人信服的预后标志物，以及一个潜在的治疗目标GC。
The purpose of this study was to investigate the clinical significance of LIMD1 and its biological roles in gastric cancer (GC). The prognostic value of LIMD1 in GC patients was determined by the online tool Kaplan–Meier Plotter. The biological functions of LIMD1 in GC were examined by in vitro assays, including proliferation, anchorage-independent growth, migration, invasion, and epithelial to mesenchymal transition (EMT) assays. The levels of downstream YAP1 regulated by LIMD1 were measured by Western blot analysis, and the sub-localization of YAP1 in GC cells was visualized by immunofluorescence staining. Differential expression levels and copy number levels of LIMD1 between GC and normal tissues were compared using the Oncomine database. A correlation of LIMD1 mRNA level and the copy number level was depicted by cBioPortal. We also evaluated the methylation status around the LIMD1 genes by Wanderer. The expression level of LIMD1 positively correlated with the prognosis of GC patients regardless of tumor stage, size, lymph node, metastasis, Lauren’s classification, differentiation, gender, treatment, and ERBB2 amplification status. Overexpression of LIMD1 impeded the tumor growth, cell motility, invasiveness, and metastasis, and knockdown of LIMD1 promoted these phenotypes in GC cells. Mechanistically, YAP1 was one of the downstream effectors of LIMD1; LIMD1 suppressed the expression of YAP1 as well as its intracellular translocation. Furthermore, we found that LIMD1 expression was reduced in some of the GC profiling datasets. Gene deletion, instead of DNA methylation, contributed to the reduced expression of LIMD1 in GC. Our results identified LIMD1 as a convincing prognostic marker as well as a potentially therapeutic target for GC.