Mieap suppresses murine intestinal tumor via its mitochondrial quality control.
Mieap suppresses murine intestinal tumor via its mitochondrial quality control.
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DOI：
10.1038/srep12472
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发表时间：
2015-07-28
影响因子：
4.6
通讯作者：
Arakawa H
中科院分区：
文献类型：
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作者：
Tsuneki M;Nakamura Y;Kinjo T;Nakanishi R;Arakawa H
Mieap 是一种新型 p53 诱导蛋白，在维持各种病理生理状态下线粒体健康方面发挥着关键作用。在这里，我们发现 ApcMin/+ 小鼠的 Mieap 缺陷与小鼠肠道肿瘤的恶性进展密切相关。为了了解 Mieap 在体内肿瘤发生中所起的作用，我们生成了 Mieap 杂合子 (ApcMin/+ Mieap+/-) 和纯合子 (ApcMin/+ Mieap−/−) ApcMin/+ 小鼠。有趣的是，具有 Mieap+/- 和 Mieap−/− 遗传背景的 ApcMin/+ 小鼠由于严重贫血，与 ApcMin/+ 小鼠相比，寿命显着缩短。肠息肉数量和大小的大幅增加与 Mieap 基因缺陷有关。组织病理学上，Mieap 缺陷的 ApcMin/+ 小鼠的肠道肿瘤清楚地表现出晚期腺瘤和腺癌。我们证明，形态不健康的线粒体的显着增加和活性氧的微量积累可能是 Mieap 缺陷 ApcMin/+ 小鼠肠道肿瘤恶性进展加剧的机制。这些发现表明，Mieap 调节的线粒体质量控制在预防小鼠肠道肿瘤发生中发挥着关键作用。
Mieap, a novel p53-inducible protein, plays a key role in maintaining healthy mitochondria in various pathophysiological states. Here, we show that Mieap deficiency in ApcMin/+ mice is strikingly associated with the malignant progression of murine intestinal tumors. To understand the role that Mieap plays in in vivo tumorigenesis, we generated Mieap heterozygous (ApcMin/+ Mieap+/−) and homozygous (ApcMin/+ Mieap−/−) ApcMin/+ mice. Interestingly, the ApcMin/+ mice with the Mieap+/− and Mieap−/− genetic background revealed remarkable shortening of the lifetime compared to ApcMin/+ mice because of severe anemia. A substantial increase in the number and size of intestinal polyps was associated with Mieap gene deficiency. Histopathologically, intestinal tumors in the Mieap-deficient ApcMin/+ mice clearly demonstrated advanced grades of adenomas and adenocarcinomas. We demonstrated that the significant increase in morphologically unhealthy mitochondria and trace accumulations of reactive oxygen species may be mechanisms underlying the increased malignant progression of the intestinal tumors of Mieap-deficient ApcMin/+ mice. These findings suggest that the Mieap-regulated mitochondrial quality control plays a critical role in preventing mouse intestinal tumorigenesis.