Analysis of a mouse model of diffuse-type gastric cancer

我们报道了一个E-cadherin/p53双条件敲除（DCKO）小鼠系，作为第一个基因工程扩散型胃癌（DGC），它在形态和分子上概括了人类DGC。最近，我们还从DCKO小鼠的原发肿瘤和淋巴结转移中建立了小鼠DGC （MDGC）细胞系。我们观察到小鼠原发性DGC中表观遗传调节因子和频繁甲基化基因的表达水平分别上调和下调。一些表观遗传抑制剂在体外诱导MDGC细胞系分化和减弱球形形成。此外，我们可以在体内验证这些药物的肿瘤抑制活性。这些结果表明，表观遗传改变可能在弥漫性胃癌发生过程中发挥重要作用，并支持制定相关的治疗策略。

We have reported an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered diffuse-type gastric cancer (DGC), which recapitulates human DGC morphologically and molecularly. Recently, we have also established mouse DGC (MDGC) cell lines from primary tumors and lymph node metastases of the DCKO mice. We observed that the expression levels of epigenetic modulators and frequently methylated genes were up- and down-regulated in mouse primary DGC, respectively. Treatment with some epigenetic inhibitors induced differentiation and attenuated sphere formation of the MDGC cell lines in vitro. Moreover, we could validate tumor-suppressing activity of these agents in vivo. These results suggest that epigenetic alterations may play significant roles in diffuse-type gastric carcinogenesis and support to develop a relevant therapeutic strategy in human DGC.