Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination.
Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination.
复制标题
人胃癌的综合分子分析将DDR2鉴定为腹膜传播的潜在调节剂。
DOI：
10.1038/srep22371
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发表时间：
2016-03-03
影响因子：
4.6
通讯作者：
Mimori K
中科院分区：
文献类型：
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作者：
Kurashige J;Hasegawa T;Niida A;Sugimachi K;Deng N;Mima K;Uchi R;Sawada G;Takahashi Y;Eguchi H;Inomata M;Kitano S;Fukagawa T;Sasako M;Sasaki H;Sasaki S;Mori M;Yanagihara K;Baba H;Miyano S;Tan P;Mimori K
腹膜播散是进展期胃癌最常见、最难治愈的转移灶。然而，驱动腹膜播散的分子机制仍然知之甚少。在这里，我们的目的是提供新的见解的分子机制，驱动GC的腹膜传播。我们对200例胃癌患者体内选择的转移细胞系和样本进行了联合表达分析，以确定腹膜播散的驱动基因。使用小鼠异种移植模型检查与GC播散相关的驱动基因功能。我们确定了一个腹膜播散相关的表达特征，其特征与发育、粘着斑和细胞外基质相关基因的特征相关。在包含表达特征的基因中，我们确定了盘状蛋白结构域受体2（DDR2）作为腹膜播散的潜在调节因子。DDR2通过DNA甲基化的丧失而上调，并且DDR2敲低减少了异种移植模型中的腹膜转移。达沙替尼是DDR2信号通路的抑制剂，可有效抑制腹膜播散。DDR2被鉴定为GC传播的驱动基因，并且可以潜在地用作抑制GC腹膜传播的新的治疗靶点。
Peritoneal dissemination is the most frequent, incurable metastasis occurring in patients with advanced gastric cancer (GC). However, molecular mechanisms driving peritoneal dissemination still remain poorly understood. Here, we aimed to provide novel insights into the molecular mechanisms that drive the peritoneal dissemination of GC. We performed combined expression analysis with in vivo-selected metastatic cell lines and samples from 200 GC patients to identify driver genes of peritoneal dissemination. The driver-gene functions associated with GC dissemination were examined using a mouse xenograft model. We identified a peritoneal dissemination-associated expression signature, whose profile correlated with those of genes related to development, focal adhesion, and the extracellular matrix. Among the genes comprising the expression signature, we identified that discoidin-domain receptor 2 (DDR2) as a potential regulator of peritoneal dissemination. The DDR2 was upregulated by the loss of DNA methylation and that DDR2 knockdown reduced peritoneal metastasis in a xenograft model. Dasatinib, an inhibitor of the DDR2 signaling pathway, effectively suppressed peritoneal dissemination. DDR2 was identified as a driver gene for GC dissemination from the combined expression signature and can potentially serve as a novel therapeutic target for inhibiting GC peritoneal dissemination.