Dobashi Yoh, Tsubochi Hiroyoshi, Minegishi Kentaro, Kitagawa Masatoshi, Otani Shinichi, Ooi Akishi
Department of Pathology, Saitama Medical Center, Jichi Medical University, Omiya, Saitama, 330-8503, Japan.
Department of Thoracic Surgery, Saitama Medical Center, Jichi Medical University, Omiya, Saitama, 330-8503, Japan.
Hum Pathol. 2017 Aug;66:67-78. doi: 10.1016/j.humpath.2017.05.022. Epub 2017 Jun 7.
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), Kip1 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.
在各种癌症中，常可见到细胞周期蛋白依赖性激酶抑制蛋白p27因降解增强而表达下调。介导这种降解的泛素连接酶已被确定为S期激酶相关蛋白2（Skp2）、Kip1泛素化促进复合物（KPC）以及含RING-H2结构域的p53诱导蛋白（Pirh2）。我们通过免疫组织化学分析，研究了这三种连接酶的表达与人类肺癌手术标本中p27状态之间的相关性。在93例病例中，p27、Skp2、KPC和Pirh2的表达分别见于89.2%、59.1%、59.1%和67.7%的病例。癌细胞中p27表达下调在腺癌（AC）和鳞状细胞癌（SCC）中较为常见，但在小细胞癌（SmCC）中未观察到。泛素连接酶的过表达在不同组织学类型中表现各异：Skp2在SCC和SmCC中更常见，KPC在SCC中更常见，Pirh2在AC中更常见，其次是SCC。我们获得了几个新发现：（i）8.6%的病例中观察到细胞质p27，最常见于SCC（13.3%），且与淋巴结转移相关（P = 0.0044）；（ii）通过统计学分析和细胞水平观察发现，细胞核p27与Pirh2表达之间存在显著负相关；（iii）在AC中，细胞质Pirh2和总（细胞质和/或细胞核）Pirh2与淋巴结状态（P = 0.0225、0.0314）、病理分期（P = 0.0213、0.0475）和无复发生存期（分别为P = 0.0194、0.0482）显著相关。总之，我们的数据表明p27及其同源泛素连接酶特别参与了临床特征，因此，对这些泛素连接酶，尤其是Pirh2进行分子靶向治疗可能对人类肺癌具有治疗价值。
