Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer.
Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer.
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DOI：
10.1038/oncsis.2015.43
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发表时间：
2016-01-04
期刊：
影响因子：
6.2
通讯作者：
Arakawa H
中科院分区：
文献类型：
--
作者：
Kamino H;Nakamura Y;Tsuneki M;Sano H;Miyamoto Y;Kitamura N;Futamura M;Kanai Y;Taniguchi H;Shida D;Kanemitsu Y;Moriya Y;Yoshida K;Arakawa H
Mieap 是一种 p53 诱导蛋白，通过修复或消除不健康的线粒体来控制线粒体质量。 BNIP3 和 NIX 是 Mieap 调节的线粒体质量控制的关键介质。 Mieap 通过其线粒体质量控制功能抑制小鼠肠道肿瘤。为了探讨 Mieap 调节的线粒体质量控制功能在结直肠癌患者中的作用，我们检测了 57 个原发性结直肠癌组织中 p53、Mieap、BNIP3 和 NIX 的状态。分别在 9% 和 47% 的结直肠癌病例中发现 Mieap 和 BNIP3 基因启动子甲基化，而在缺乏 Mieap 和 BNIP3 启动子甲基化的结直肠癌组织中，超过 50% 发现 p53 突变，这意味着 p53/Mieap/BNIP3 调节的线粒体质量控制通路在超过 70% 的结直肠癌组织中失活。 结直肠癌患者。在 LS174T 结直肠癌细胞中，缺氧激活了 Mieap 调节的线粒体质量控制功能。 LS174T细胞中p53、Mieap或BNIP3的敲低严重损害了缺氧激活功能，导致不健康线粒体的积累和线粒体活性氧生成的增加。 p53/Mieap/BNIP3缺陷细胞中不健康线粒体产生的线粒体活性氧显着增强缺氧条件下癌细胞的迁移和侵袭。这些结果表明，Mieap 调节的线粒体质量控制在体内缺氧肿瘤微环境中抑制结直肠癌中具有关键作用。
Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. BNIP3 and NIX are critical mediators for the Mieap-regulated mitochondrial quality control. Mieap suppresses murine intestinal tumor via its mitochondrial quality control function. To explore the role of the Mieap-regulated mitochondria quality control function in colorectal cancer patients, we examined the statuses of p53, Mieap, BNIP3 and NIX in 57 primary colorectal cancer tissues. Promoter methylation of the Mieap and BNIP3 genes was found in 9% and 47% of colorectal cancer cases, respectively, whereas p53 mutation was found in more than 50% of colorectal cancer tissues lacking methylation of the Mieap and BNIP3 promoters, implying that the p53/Mieap/BNIP3-regulated mitochondria quality control pathway is inactivated in more than 70% of colorectal cancer patients. In LS174T colorectal cancer cells, hypoxia activated the Mieap-regulated mitochondria quality control function. Knockdown of p53, Mieap or BNIP3 in LS174T cells severely impaired the hypoxia-activated function, leading to the accumulation of unhealthy mitochondria and increase of mitochondrial reactive oxygen species generation. The mitochondrial reactive oxygen species generated by unhealthy mitochondria in the p53/Mieap/BNIP3-deficient cells remarkably enhanced cancer cell migration and invasion under hypoxic condition. These results suggest that the Mieap-regulated mitochondria quality control has a critical role in colorectal cancer suppression in the in vivo hypoxic tumor microenvironment.