Regulation of p27 by ubiquitin ligases and its pathological significance in human lung carcinomas
Regulation of p27 by ubiquitin ligases and its pathological significance in human lung carcinomas
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DOI：
10.1016/j.humpath.2017.05.022
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发表时间：
2017-08-01
期刊：
影响因子：
3.3
通讯作者：
Ooi, Akishi
中科院分区：
文献类型：
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作者：
Dobashi, Yoh;Tsubochi, Hiroyoshi;Ooi, Akishi
细胞周期蛋白依赖性激酶抑制剂蛋白p27由于降解增强而下调，在各种癌症中经常观察到。介导这种降解的泛素连接酶已被鉴定为S期激酶相关蛋白2（Skp 2）、Kip 1泛素化促进复合物（KPC）和具有RING-H2结构域的p53诱导蛋白（Pirh 2）。我们通过免疫组化分析研究了这三种连接酶的表达与人肺癌手术标本中p27状态之间的相关性。93例中p27、Skp 2、KPC和Pirh 2的阳性表达率分别为89.2%、59.1%、59.1%和67.7%。癌细胞中p27的下调在腺癌（AC）和鳞状细胞癌（SCC）中经常观察到，但在小细胞癌（SmCC）中未观察到。泛素连接酶的过度表达在不同的组织学类型中观察到：Skp 2在SCC和SmCC中更常见，KPC在SCC中更常见，Pirh 2在AC中更常见，其次是SCC。获得了一些新的发现：（i）8.6%的患者可见胞浆p27，最常见于SCC（13.3%），与淋巴结转移有关（P = 0.0044），（ii）通过统计学分析和在细胞水平上观察到核p27和Pirh 2表达之间的显著负相关，和（iii）细胞质Pirh 2和总Pirh Pirh 2（胞浆和/或胞核）与淋巴结状态显著相关AC中的病理分期（P = 0.0213，0.0475）和无复发生存率（分别为P = 0.0194，0.0482）。总之，我们的数据表明，p27和它的同源泛素连接酶是专门参与的临床概况，因此，这些泛素连接酶，特别是Pirh 2的分子靶向，可能对人类肺癌的治疗价值。(C)2017爱思唯尔公司All rights reserved.
Down-regulation of cyclin-dependent kinase inhibitor protein p27, due to enhanced degradation, is frequently observed in various cancers. The ubiquitin ligases that mediate this degradation have been identified as S-phase kinase-associated protein-2 (Skp2), Kip 1 ubiquitylation-promoting complex (KPC), and p53-inducible protein with RING-H2 domain (Pirh2) as well. We investigated the correlation among expression of these 3 ligases and p27 status in surgical specimens of human lung carcinomas by immunohistochemical analysis. Among 93 cases, expressions of p27, Skp2, KPC, and Pirh2 were found in 89.2%, 59.1%, 59.1%, and 67.7%, respectively. Down-regulation of p27 in cancer cells was frequently observed in adenocarcinoma (AC) and squamous cell carcinoma (SCC), but not in small cell carcinoma (SmCC). Overexpression of ubiquitin ligases was variously observed among histological types: Skp2 was more frequently observed in SCC and SmCC, KPC in SCC and Pirh2 in AC, followed by SCC. Several novel findings were obtained: (i) cytoplasmic p27 was observed in 8.6%, most frequently in SCC (13.3%), and correlated with nodal metastasis (P = .0044), (ii) significant inverse correlation between nuclear p27 and Pirh2 expression was observed by statistical analysis and at the cellular level, and (iii) cytoplasmic Pirh2 and total (cytoplasmic and/or nuclear) Pirh2 were significantly correlated with the nodal status (P = .0225, 0.0314), the pathological stage (P = .0213, 0.0475) and recurrence-free survival (P = .0194, 0.0482, respectively) in AC. Altogether, our data suggests that p27 and its cognate ubiquitin ligases are specifically involved in the clinical profiles, and thus, molecular targeting of these ubiquitin ligases, in particular, Pirh2, may have therapeutic value for human lung carcinomas. (C) 2017 Elsevier Inc. All rights reserved.