Department of Medicine, Division of Gastroenterology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Oncogene. 2012 Apr 5;31(14):1771-80. doi: 10.1038/onc.2011.362. Epub 2011 Aug 15.
The cyclin-dependent kinase (CDK) inhibitor p27 has an important role in cell cycle regulation. Reduced expression of p27 is commonly associated with poor prognosis in many malignancies, including gastric cancer. Cytoplasmic p27 mislocalization may be an additional indicator of high-grade tumors and poor prognosis in cancer. As chronic infection by Helicobacter pylori is the most important risk factor for gastric cancer development, we evaluated the effects of H. pylori on p27 expression and localization in gastric cancer cells. Co-culture of gastric cells with H. pylori induced cytoplasmic p27 expression and reduced nuclear p27 expression in vitro. Cytoplasmic p27 expression was associated with and dependent upon phosphorylation of p27 at T157 and T198: wild-type p27 accumulated in the cytoplasm, but non-phosphorylatable mutants affecting T157 or T198 were nuclear in H. pylori-infected cells. These post-translational p27 changes were secondary to activation of cellular phosphoinositide-3 kinase (PI3K) and AKT signaling pathways, and dependent upon a functional H. pylori cag pathogenicity island. We investigated the clinical significance of cytoplasmic p27 mislocalization in 164 cases of resected gastric cancer in tissue microarrays. In 97 cases (59%), cytoplasmic p27 mislocalization was observed, and this was associated with increased mortality in multivariate analysis. These results show that H. pylori infection induces AKT/PI3K-mediated phosphorylation of p27 at T157 and T198 to cause cytoplasmic p27 mislocalization in gastric cancer, and that p27 mislocalization is an adverse prognostic feature in gastric cancer. This is the first demonstration of the translocation of a specific bacterial virulence factor that post-translationally regulates a host cell CDK inhibitor. This is of particular significance, because p27 has both tumor-suppressive and oncogenic activities, depending upon its subcellular localization. Cytoplasmic mislocalization of p27 induced by H. pylori may be an important mechanistic link between H. pylori infection and gastric carcinogenesis.
细胞周期蛋白依赖性激酶（CDK）抑制剂 p27 在细胞周期调控中起着重要作用。p27 表达降低通常与许多恶性肿瘤包括胃癌的预后不良有关。细胞质 p27 定位异常可能是肿瘤分级较高和癌症预后不良的另一个指标。由于幽门螺杆菌（H. pylori）的慢性感染是胃癌发展的最重要危险因素，我们评估了 H. pylori 对胃癌细胞中 p27 表达和定位的影响。体外共培养胃细胞与 H. pylori 诱导细胞质 p27 表达，并降低核内 p27 表达。细胞质 p27 表达与 p27 在 T157 和 T198 位点的磷酸化有关，并且依赖于磷酸化：野生型 p27 在 H. pylori 感染的细胞中积累在细胞质中，但影响 T157 或 T198 的非磷酸化突变体在细胞中是核定位的。这些翻译后 p27 变化是细胞内磷酸肌醇-3 激酶（PI3K）和 AKT 信号通路激活的结果，并且依赖于功能性 H. pylori cag 致病岛。我们在组织微阵列中研究了 164 例胃癌切除标本中细胞质 p27 定位异常的临床意义。在 97 例（59%）中观察到细胞质 p27 定位异常，并且在多变量分析中与死亡率增加有关。这些结果表明，H. pylori 感染诱导 AKT/PI3K 介导的 p27 在 T157 和 T198 位点的磷酸化，导致胃癌中细胞质 p27 定位异常，并且 p27 定位异常是胃癌的不良预后特征。这是首次证明特定细菌毒力因子的易位可以翻译后调节宿主细胞 CDK 抑制剂。这具有特别重要的意义，因为 p27 的亚细胞定位取决于其抑癌和致癌活性。H. pylori 诱导的 p27 细胞质定位异常可能是 H. pylori 感染与胃癌发生之间的重要机制联系。
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