Tsuneki Masayuki, Nakamura Yasuyuki, Kinjo Takao, Nakanishi Ruri, Arakawa Hirofumi
Division of Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Division of Morphological Pathology, Department of Basic Laboratory Sciences, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
Sci Rep. 2015 Jul 28;5:12472. doi: 10.1038/srep12472.
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 Apc(Min/+) 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 (Apc(Min/+) Mieap(+/-)) and homozygous (Apc(Min/+) Mieap(-/-)) Apc(Min/+) mice. Interestingly, the Apc(Min/+) mice with the Mieap(+/-) and Mieap(-/-) genetic background revealed remarkable shortening of the lifetime compared to Apc(Min/+) 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 Apc(Min/+) 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 Apc(Min/+) mice. These findings suggest that the Mieap-regulated mitochondrial quality control plays a critical role in preventing mouse intestinal tumorigenesis.
Mieap是一种新型的p53诱导蛋白，在多种病理生理状态下维持健康的线粒体方面发挥着关键作用。在此，我们表明Apc(Min/+)小鼠中的Mieap缺陷与小鼠肠道肿瘤的恶性进展显著相关。为了了解Mieap在体内肿瘤发生中的作用，我们构建了Mieap杂合子（Apc(Min/+) Mieap(+/-)）和纯合子（Apc(Min/+) Mieap(-/-)）的Apc(Min/+)小鼠。有趣的是，与Apc(Min/+)小鼠相比，具有Mieap(+/-)和Mieap(-/-)基因背景的Apc(Min/+)小鼠由于严重贫血，寿命显著缩短。肠道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Apc(Min/+)小鼠的肠道肿瘤明显表现为高级别腺瘤和腺癌。我们证明，形态不健康的线粒体显著增加和活性氧的微量积累可能是Mieap缺陷的Apc(Min/+)小鼠肠道肿瘤恶性进展增加的潜在机制。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起关键作用。
