Potential role of jun activation domain-binding protein 1 as a negative regulator of p27kip1 in pancreatic adenocarcinoma
Potential role of jun activation domain-binding protein 1 as a negative regulator of p27kip1 in pancreatic adenocarcinoma
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DOI：
10.1158/0008-5472.can-06-0975
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发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Claret, Francois X.
中科院分区：
文献类型：
--
作者：
Kouvaraki, Maria A.;Korapati, Anita L.;Claret, Francois X.
p27 表达减少与大多数人类癌症（包括胰腺腺癌）的不良预后相关。 Jun 激活结构域结合蛋白 1 (JAB1) 是一种激活蛋白 (AP-1) 共激活因子，之前与 p27 降解有关，在多种肿瘤中过度表达，并与 p27 低表达相关。我们检查了正常和肿瘤性胰腺组织中的 JAB1 和 p27。在胰腺癌样本中观察到 JAB1 表达增加，但在配对的正常胰腺组织中未观察到。使用组织微阵列进行的免疫组织化学分析显示，JAB1 在所测试的所有 32 个（100%）胰腺腺癌样本中均过表达，其中 23 个（72%）样本中主要在细胞核中，在 9 个（28%）个肿瘤中主要在细胞质中。当使用 10% 作为 p27 阳性的截止值时，p27 在 11 个肿瘤（34%）中表达；然而，仅 4 个（13%）样本中 p27 表达位于肿瘤细胞的细胞核中。 JAM 在胰腺癌细胞系 Panc-1、Mia PaCa-2 和 Panc-28 中的过度表达导致 p27 表达减少。相反，短干扰RNA下调JAB1会显着增加p27表达并抑制细胞周期从G期进展到S期。有趣的是，当 S 期激酶相互作用蛋白 2 (Skp2)（一种 p27 泛素化和随后降解所需的 F-box 蛋白）被沉默时，JAB1 介导的 p27 降解并未受到损害。因此，JAB1在胰腺癌细胞中可能具有不依赖于Skp2的p27降解机制。这些发现表明，JAB1 过表达通过 JAB1 介导的 p27 降解参与胰腺癌的发病机制，并且控制 JAB1 表达是胰腺癌患者的新治疗靶点。
Reduced expression of p27 has been associated with poor prognosis in most human cancers, including pancreatic adenocarcinoma. Jun activation domain-binding protein 1 (JAB1), an activator protein (AP-1) coactivator, previously implicated in p27 degradation, is overexpressed in various tumors and correlates with low p27 expression. We examined JAB1 and p27 in normal and neoplastic pancreatic tissues. Increased JAB1 expression was seen in pancreatic carcinoma samples but not in paired normal pancreatic tissues. Immunohistochemical analysis using tissue microarrays showed that JAB1 was overexpressed in all 32 (100%) pancreatic adenocarcinoma samples tested, predominantly nuclear in 23 (72%) samples and predominantly cytoplasmic in 9 (28%) tumors. When 10% was used as a cutoff for p27 positivity, p27 was expressed in 11 (34%) of tumors; however, p27 expression was localized in the nuclei of tumor cells in only 4 (13%) of the samples. Overexpression of the JAM in the pancreatic carcinoma cell lines Panc-1, Mia PaCa-2, and Panc-28 resulted in decreased p27 expression. Conversely, down-regulation of JAB1 by short interfering RNA substantially increased p27 expression and inhibited progression from G, to S phase of the cell cycle. Interestingly, JAB1-mediated p27 degradation was not impaired when S-phase kinase-interacting protein 2 (Skp2), an F-box protein required for the ubiquitination and consequent degradation of p27, was silenced. Thus, JAB1 may have an Skp2-independent p27 degradation mechanism in pancreatic cancer cells. These findings suggest that JAB1 overexpression is involved in the pathogenesis of pancreatic cancer through JAB1-mediated p27 degradation and that control of JAB1 expression is a novel therapeutic target in patients with pancreatic adenocarcinomas.