Frequent amplification of <i>PTP1B</i> is associated with poor survival of gastric cancer patients

The protein tyrosine phosphatase 1B (<i>PTP1B</i>), a non-transmembrane protein tyrosine phosphatase, has been implicated in gastric pathogenesis. Several lines of recent evidences have shown that <i>PTP1B</i> is highly amplified in breast and prostate cancers. The aim of this study was to investigate <i>PTP1B</i> amplification in gastric cancer and its association with poor prognosis of gastric cancer patients, and further determine the role of <i>PTP1B</i> in gastric tumorigenesis. Our data demonstrated that <i>PTP1B</i> was significantly up-regulated in gastric cancer tissues as compared with matched normal gastric tissues by using quantitative RT-PCR (qRT-PCR) assay. In addition, copy number analysis showed that <i>PTP1B</i> was amplified in 68/131 (51.9%) gastric cancer cases, whereas no amplification was found in the control subjects. Notably, <i>PTP1B</i> amplification was positively associated with its protein expression, and was significantly related to poor survival of gastric cancer patients. Knocking down <i>PTP1B</i> expression in gastric cancer cells significantly inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrested and apoptosis. Mechanically, <i>PTP1B</i> promotes gastric cancer cell proliferation, survival and invasiveness through modulating Src-related signaling pathways, such as Src/Ras/MAPK and Src/phosphatidylinositol-3-kinase (PI3K)/Akt pathways. Collectively, our data demonstrated frequent overexpression and amplification <i>PTP1B</i> in gastric cancer, and further determined the oncogenic role of <i>PTP1B</i> in gastric carcinogenesis. Importantly, <i>PTP1B</i> amplification predicts poor survival of gastric cancer patients.蛋白酪氨酸磷酸酶1B（protein tyrosine phosphatase 1B，PTP1B）是一种非跨膜型蛋白酪氨酸磷酸酶，已被证实与胃部疾病的发病机制密切相关。近期多项研究证据表明，PTP1B在乳腺癌与前列腺癌中存在高频扩增现象。本研究旨在探讨胃癌组织中PTP1B的扩增情况及其与胃癌患者不良预后的关联，并进一步明确PTP1B在胃癌发生发展中的作用。本研究通过定量逆转录聚合酶链反应（quantitative RT-PCR，qRT-PCR）检测发现，相较于配对的正常胃组织，胃癌组织中PTP1B的表达水平显著上调。此外，拷贝数分析结果显示，131例胃癌患者中有68例（51.9%）存在PTP1B扩增，而对照受试者中未检测到该扩增。值得注意的是，PTP1B扩增与其蛋白表达水平呈正相关，且与胃癌患者的不良生存期显著相关。在胃癌细胞中敲低PTP1B的表达，可显著抑制细胞增殖、集落形成、迁移与侵袭能力，并诱导细胞周期阻滞与细胞凋亡。机制研究表明，PTP1B通过调控Src相关信号通路，例如Src/Ras/MAPK及Src/磷脂酰肌醇3-激酶（phosphatidylinositol-3-kinase，PI3K）/Akt通路，促进胃癌细胞的增殖、存活与侵袭能力。综上，本研究证实胃癌组织中存在PTP1B的高频过表达与扩增，进一步明确了PTP1B在胃癌发生中的致癌作用。尤为重要的是，PTP1B扩增可有效预测胃癌患者的不良生存期。