Fukumoto Akihisa, Ikeda Naoya, Sho Masayuki, Tomoda Kiichiro, Kanehiro Hiromichi, Hisanaga Michiyoshi, Tsurui Yoshikazu, Tsutsumi Masahiro, Kato Jun-Ya, Nakajima Yoshiyuki
First Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-city, Nara 634-8522, Japan.
Oncol Rep. 2004 Feb;11(2):277-84.
p27Kip1 belongs to the family of small polypeptides collectively termed cyclin-dependent kinase inhibitors, which negatively regulate the cell cycle progression. In various human cancers, the reduced p27Kip1 expression correlates well with poor prognosis. Recently, Jab1/CSN5, the fifth component of the COP9 signalosome complex, was found to specifically translocate p27Kip1 from the nucleus to the cytoplasm, and reduce the protein level of p27Kip1 by accelerating its degradation. In this study, we investigated the expression of p27Kip1 and Jab1 in 61 cases with pancreatic ductal adenocarcinoma. The p27Kip1 expression was positive in 41% (25/61) of the tumors. Of the 25 positive tumors, 12 cases had p27Kip1 positive expression mainly in the nucleus of the tumor cells, while 13 cases had p27Kip1 in the cytoplasm as well as in the nucleus. Among a variety of clinicopathological factors, only tumor status was inversely correlated with p27Kip1 expression (p=0.019). The Jab1 expression was detected both in the nucleus and the cytoplasm in almost all pancreatic cancer cells. The intensity of Jab1 expression in tumor cells, especially in the cytoplasm, was much stronger than in normal pancreatic ductal epithelial cells. The patients with positive p27Kip1 expression had significantly better prognosis than ones with negative p27Kip1 expression (p=0.008). Furthermore, 12 patients with exclusively nuclear p27Kip1 expression, but not 13 patients with both nuclear and cytoplasmic p27Kip1 expression, had significantly better prognosis than 36 patients with negative p27Kip1 expression (p=0.009). In multivariate survival analysis, localized p27Kip1 expression was an independent prognostic factor (p=0.016). The results of our study suggested that the mislocalization as well as the downregulation of p27Kip1 had significant prognostic value in pancreatic cancer and that Jab1 might play an important role in carcinogenesis of pancreatic cancer. Cell cycle control targeting p27Kip1 might be a promising future therapeutic modality against pancreatic cancer.
p27Kip1属于一类统称为细胞周期蛋白依赖性激酶抑制剂的小多肽家族，它们对细胞周期进程起负向调节作用。在多种人类癌症中，p27Kip1表达降低与预后不良密切相关。最近发现，COP9信号体复合物的第五个组分Jab1/CSN5能特异性地将p27Kip1从细胞核转运至细胞质，并通过加速其降解来降低p27Kip1的蛋白水平。在本研究中，我们调查了61例胰腺导管腺癌患者中p27Kip1和Jab1的表达情况。41%（25/61）的肿瘤中p27Kip1表达呈阳性。在这25例阳性肿瘤中，12例主要在肿瘤细胞核中呈p27Kip1阳性表达，而13例在细胞质及细胞核中均有p27Kip1表达。在各种临床病理因素中，只有肿瘤状态与p27Kip1表达呈负相关（p = 0.019）。几乎所有胰腺癌细胞的细胞核和细胞质中均检测到Jab1表达。肿瘤细胞中Jab1的表达强度，尤其是在细胞质中的表达强度，比正常胰腺导管上皮细胞中的要强得多。p27Kip1表达阳性的患者预后明显好于p27Kip1表达阴性的患者（p = 0.008）。此外，仅细胞核中有p27Kip1表达的12例患者，而非细胞核和细胞质中均有p27Kip1表达的13例患者，其预后明显好于p27Kip1表达阴性的36例患者（p = 0.009）。在多因素生存分析中，局部p27Kip1表达是一个独立的预后因素（p = 0.016）。我们的研究结果表明，p27Kip1的定位错误及下调在胰腺癌中具有显著的预后价值，并且Jab1可能在胰腺癌的发生发展中起重要作用。以p27Kip1为靶点的细胞周期调控可能是未来治疗胰腺癌的一种有前景的治疗方式。
