High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers
High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers
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DOI：
10.1111/j.1349-7006.2009.01122.x
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发表时间：
2009-05-01
期刊：
影响因子：
5.7
通讯作者：
Kitagawa, Masatoshi
中科院分区：
文献类型：
--
作者：
Shimada, Mai;Kitagawa, Kyoko;Kitagawa, Masatoshi
由于细胞周期蛋白依赖性激酶抑制蛋白 p27 降解的增强，在各种癌症中经常观察到细胞周期蛋白依赖性激酶抑制蛋白 p27 的下调。我们最近报道，具有 RING-H2 结构域的 p53 诱导蛋白 (Pirh2) 是一种新型 p27 泛素连接酶，是 p27 蛋白泛素化和随后降解所必需的。然而，目前还没有关于 Pirh2 参与 p27 下调和人类癌症发病机制的报道。在本研究中，我们使用来自人头颈鳞状细胞癌（HNSCC）的培养细胞系和手术标本对它们进行了研究。通过短干扰RNA消除Pirh2可诱导p27的积累并抑制培养的HNSCC细胞的生长。通过对 57 例 HNSCC 标本进行免疫组织化学分析，发现 61.4% 的 HNSCC 中 Pirh2 表达水平较高（标记指数≥ 60%），而正常粘膜的表达水平为 0%。此外，83.3% 的 p27 表达较低（标记指数 < 20%）的 HNSCC 显示出较高的 Pirh2 水平。因此，Pirh2表达与p27表达呈负相关。最后，Pirh2 表达与不良预后密切相关。这些发现表明，Pirh2 过表达可能在 HNSCC 的发生和维持中发挥重要作用，至少部分是通过 p27 降解实现的，并且 Pirh2 可能是人类 HNSCC 的潜在分子靶标。 （《癌症科学》2009 年；100：866-872）。
Downregulation of the cyclin-dependent kinase inhibitory protein p27 is frequently observed in various cancers due to enhancement of its degradation. We recently reported that p53-inducible protein with RING-H2 domain (Pirh2) is a novel ubiquitin ligase for p27, required for the ubiquitylation and consequent degradation of p27 protein. However, there is no reports about the involvement of Pirh2 in both p27 downregulation and pathogenesis in human cancers. In the present study, we investigated them using cultured cell lines and surgical specimens derived from human head and neck squamous cell carcinoma (HNSCC). Depletion of Pirh2 by short interfering RNA induced accumulation of p27 and inhibited the growth of cultured HNSCC cells. By immunohistochemical analysis in 57 cases of HNSCC specimens, higher levels of Pirh2 expression (labeling index >= 60%) were found in 61.4% of HNSCC in comparison with 0% of normal mucosa. In addition, 83.3% of HNSCC with lower p27 expression (labeling index < 20%) displayed high Pirh2 levels. Therefore, Pirh2 expression was inversely correlated with p27 expression. Finally, Pirh2 expression was well correlated with poor prognosis. These findings suggest that Pirh2 overexpression may have an important role in the development and maintenance of HNSCC at least partially through p27 degradation, and that Pirh2 may be a potential molecular target for human HNSCC. (Cancer Sci 2009; 100: 866-872).