p53/Mieap-regulated mitochondrial quality control plays an important role as a tumor suppressor in gastric and esophageal cancers
p53/Mieap-regulated mitochondrial quality control plays an important role as a tumor suppressor in gastric and esophageal cancers
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DOI：
10.1016/j.bbrc.2020.05.168
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发表时间：
2020-08-27
影响因子：
3.1
通讯作者：
Yoshida, Kazuhiro
中科院分区：
文献类型：
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作者：
Sano, Hitoya;Futamura, Manabu;Yoshida, Kazuhiro
线粒体吞噬蛋白 (Mieap) 在线粒体质量控制 (MQC) 中发挥着关键作用，并作为 p53 诱导型肿瘤抑制因子发挥作用。本研究旨在探讨其在胃癌（GC）和食道癌（EC）中的作用。 GC 细胞用 Mieap 过表达腺病毒 (Ad-Mieap) 感染，并进行荧光激活细胞分选 (FACS)、蛋白质印迹和 caspase 测定。此后，我们评估了体内 p53/Mieap 调节的 MQC 通路的潜在破坏。对 Mieap、NIX 和 BNIP3 启动子进行甲基化特异性 PCR (MSP)，并使用冷冻保存的手术标本检测 p53 突变。 GC 细胞中的外源 Mieap 诱导液泡样结构（称为 MIV，Mieap 诱导的液泡）的形成和 caspase 依赖性细胞死亡，同时激活 caspase-3 和 caspase-9。在 47 名 GC 患者中，分别在 2 名 (4.3%)、29 名 (61.7%) 和零名 (0%) 样本中发现了 Mieap、BNIP3 和 NIX 启动子甲基化。总共有 33 名 GC 患者 (70.2%) 使该 MQC 通路失活。令人惊讶的是，47 名 GC 患者中有 18 名 (38.3%) 正常上皮中的 BNIP3 启动子高度甲基化。在 EC 患者中，12 名患者中有 10 名 (83.3%) 的 MQC 通路也失活。这些结果表明，p53/Mieap 调节的 MQC 在上消化道 (GI) 肿瘤抑制中发挥着重要作用，部分可能是通过线粒体凋亡途径实现的。 (C) 2020 作者。由爱思唯尔公司出版
Mitochondria-eating protein (Mieap) plays a critical role in mitochondrial quality control (MQC) and functions as a p53-inducible tumor suppressor. This study aimed to examine its role in gastric cancer (GC) and esophageal cancer (EC). GC cells were infected with Mieap-overexpressing adenovirus (Ad-Mieap) and subjected to fluorescence-activated cell sorting (FACS), western blotting, and caspase assays. Thereafter, we evaluated the potential disruption of the p53/Mieap-regulated MQC pathway in vivo. Methylation-specific PCR (MSP) for Mieap, NIX, and BNIP3 promoters was performed and p53 mutations were detected using cryopreserved surgical specimens. Exogenous Mieap in GC cells induced the formation of vacuole-like structures (called MIVs, Mieap-induced vacuoles) and caspase-dependent cell death, with the activation of both caspase-3 and caspase-9. Of the 47 GC patients, promoter methylation in Mieap, BNIP3, and NIX was identified in two (4.3%), 29 (61.7%), and zero (0%) specimens, respectively. In total, 33 GC patients (70.2%) inactivated this MQC pathway. Amazingly, BNIP3 promoter in the normal epithelium was highly methylated in 18 of the 47 GC patients (38.3%). In EC patients, this MQC pathway was also inactivated in ten of 12 patients (83.3%). These results indicate that p53/Mieap-regulated MQC plays an important role in upper gastrointestinal (GI) tumor suppression, possibly, in part, through the mitochondrial apoptotic pathway. (C) 2020 The Authors. Published by Elsevier Inc.