Inhibition of DNA Methylation Suppresses Intestinal Tumor Organoids by Inducing an Anti-Viral Response.
Inhibition of DNA Methylation Suppresses Intestinal Tumor Organoids by Inducing an Anti-Viral Response.
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DOI：
10.1038/srep25311
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发表时间：
2016-05-04
影响因子：
4.6
通讯作者：
Saito H
中科院分区：
文献类型：
--
作者：
Saito Y;Nakaoka T;Sakai K;Muramatsu T;Toshimitsu K;Kimura M;Kanai T;Sato T;Saito H
最近的研究提出，DNA甲基化抑制剂的主要抗肿瘤作用是通过含有dsRNA的内源性逆转录病毒诱导干扰素反应基因。最近，开发了一种称为类器官培养的干细胞 3D 培养系统。 Lgr5 阳性干细胞形成的类器官密切再现了原始组织的特性。为了研究 DNA 去甲基化对肿瘤类器官的影响，我们从 ApcMin/+ (Min) 小鼠的肠道肿瘤中建立了类器官，并对它们进行 5-aza-2'-脱氧胞苷 (5-Aza-CdR) 处理和 Dnmt1 敲低。 5-Aza-CdR 处理和 Dnmt1 敲除诱导的 DNA 去甲基化显着降低了肿瘤类器官的细胞增殖。 5-Aza-CdR 处理和 Dnmt1 敲除后肿瘤类器官的微阵列分析表明，干扰素反应基因通过 DNA 去甲基化被激活。基因本体论和通路分析清楚地表明，这些由 DNA 去甲基化激活的基因参与了抗病毒反应。这些发现表明，DNA 去甲基化通过诱导抗病毒反应（包括激活干扰素反应基因）来抑制肠道肿瘤类器官的增殖。使用 DNA 甲基化抑制剂治疗以激活生长抑制免疫反应可能是结肠癌的有效治疗方法。
Recent studies have proposed that the major anti-tumor effect of DNA methylation inhibitors is induction of interferon-responsive genes via dsRNAs-containing endogenous retroviruses. Recently, a 3D culture system for stem cells known as organoid culture has been developed. Lgr5-positive stem cells form organoids that closely recapitulate the properties of original tissues. To investigate the effect of DNA demethylation on tumor organoids, we have established organoids from intestinal tumors of ApcMin/+ (Min) mice and subjected them to 5-aza-2′-deoxycytidine (5-Aza-CdR) treatment and Dnmt1 knockdown. DNA demethylation induced by 5-Aza-CdR treatment and Dnmt1 knockdown significantly reduced the cell proliferation of the tumor organoids. Microarray analyses of the tumor organoids after 5-Aza-CdR treatment and Dnmt1 knockdown revealed that interferon-responsive genes were activated by DNA demethylation. Gene ontology and pathway analyses clearly demonstrated that these genes activated by DNA demethylation are involved in the anti-viral response. These findings indicate that DNA demethylation suppresses the proliferation of intestinal tumor organoids by inducing an anti-viral response including activation of interferon-responsive genes. Treatment with DNA methylation inhibitors to activate a growth-inhibiting immune response may be an effective therapeutic approach for colon cancers.