Possible role of p53/Mieap-regulated mitochondrial quality control as a tumor suppressor in human breast cancer.
Possible role of p53/Mieap-regulated mitochondrial quality control as a tumor suppressor in human breast cancer.
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DOI：
10.1111/cas.13824
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发表时间：
2018-12
期刊：
影响因子：
5.7
通讯作者：
Yoshida K
中科院分区：
文献类型：
--
作者：
Gaowa S;Futamura M;Tsuneki M;Kamino H;Tajima JY;Mori R;Arakawa H;Yoshida K
由p53靶基因编码的线粒体进食蛋白（Mieap）在线粒体质量控制（MQC）中起着重要作用。据报道，Mieap在结直肠癌的肿瘤抑制中具有关键作用。在这里，我们研究了它作为乳腺癌肿瘤抑制因子的作用。乳腺癌细胞中外源性Mieap的强制表达诱导了caspase依赖性凋亡，并激活了caspase-3/7和caspase-9。免疫组化显示24/75（32%）例浸润性导管癌（IDC）、15/27（55.6%）例导管原位癌（DCIS）和16/18（88.9%）例纤维腺瘤（FA）的胞浆中存在内源性Mieap（IDC vs DCIS; P = 0.0389，DCIS vs FA; P = 0.0234，IDC vs FA; P <0.0001）。在IDC中，Mieap启动子在6/46（13%）例中甲基化，而p53在6/46（13%）例中突变。因此，p53/Mieap调节的MQC途径在12/46例IDC中失活（26.1%）。有趣的是，所有来自12名Mieap启动子甲基化或p53突变患者的肿瘤在病理学上表现出更具侵袭性和恶性的乳腺癌表型。p53/Mieap调节的MQC通路受损导致无病生存期（DFS）显著缩短（P = 0.021），尽管p53状态在DFS中比Mieap启动子甲基化更具预后性。这些结果表明，p53/Mieap调节的MQC在乳腺癌的肿瘤抑制中具有关键作用，可能部分通过线粒体凋亡途径。
Mitochondria‐eating protein (Mieap), encoded by a p53‐target gene, plays an important role in mitochondrial quality control (MQC). Mieap has been reported to have a critical role in tumor suppression in colorectal cancer. Here, we investigated its role as a tumor suppressor in breast cancer. The enforced expression of exogenous Mieap in breast cancer cells induced caspase‐dependent apoptosis, with activation of both caspase‐3/7 and caspase‐9. Immunohistochemistry revealed endogenous Mieap in the cytoplasm in 24/75 (32%) invasive ductal carcinomas (IDC), 15/27 (55.6%) cases of ductal carcinoma in situ (DCIS) and 16/18 (88.9%) fibroadenomas (FA) (IDC vs DCIS; P = 0.0389, DCIS vs FA; P = 0.0234, IDC vs FA; P < 0.0001). In IDC, the Mieap promoter was methylated in 6/46 (13%) cases, whereas p53 was mutated in 6/46 (13%) cases. Therefore, the p53/Mieap‐regulated MQC pathway was inactivated in 12/46 IDC (26.1%). Interestingly, all tumors derived from the 12 patients with Mieap promoter methylation or p53 mutations pathologically exhibited more aggressive and malignant breast cancer phenotypes. Impairment of p53/Mieap‐regulated MQC pathway resulted in significantly shorter disease‐free survival (DFS) (P = 0.021), although p53 status is more prognostic in DFS than Mieap promoter methylation. These results indicate that p53/Mieap‐regulated MQC has a critical role in tumor suppression in breast cancer, possibly in part through mitochondrial apoptotic pathway.
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影响因子：
6.2
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
通讯作者：
Arakawa H
p53对预测乳腺癌内脏转移患者临床结局的影响
影响因子：
4.6
作者：
Yang, P.;Du, C. W.;Kwan, M.;Liang, S. X.;Zhang, G. J.
通讯作者：
Zhang, G. J.
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
64.8
作者：
Tanaka, H;Arakawa, H;Nakamura, Y
通讯作者：
Nakamura, Y
线粒体内可能存在溶酶体样细胞器及其在线粒体质量控制中的作用。
影响因子：
3.7
作者：
Miyamoto Y;Kitamura N;Nakamura Y;Futamura M;Miyamoto T;Yoshida M;Ono M;Ichinose S;Arakawa H
通讯作者：
Arakawa H