Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
Mol Cancer. 2010 Sep 21;9:253. doi: 10.1186/1476-4598-9-253.
Trop2 is a cell-surface glycoprotein overexpressed by a variety of epithelial carcinomas with reported low to restricted expression in normal tissues. Expression of Trop2 has been associated with increased tumor aggressiveness, metastasis and decreased patient survival, but the signaling mechanisms mediated by Trop2 are still unknown. Here, we studied the effects murine Trop2 (mTrop2) exerted on tumor cellular functions and some of the signaling mechanisms activated by this oncogene.
mTrop2 expression significantly increased tumor cell proliferation at low serum concentration, migration, foci formation and anchorage-independent growth. These in vitro characteristics translated to increased tumor growth in both subcutaneous and orthotopic pancreatic cancer murine models and also led to increased liver metastasis. mTrop2 expression also increased the levels of phosphorylated ERK1/2 mediating cell cycle progression by increasing the levels of cyclin D1 and cyclin E as well as downregulating p27. The activation of ERK was also observed in human pancreatic ductal epithelial cells and colorectal adenocarcinoma cells overexpressing human Trop2.
These findings demonstrate some of the pathogenic effects mediated by mTrop2 expression on cancer cells and the importance of targeting this cell surface glycoprotein. This study also provides the first indication of a molecular signaling pathway activated by Trop2 which has important implications for cancer cell growth and survival.
Trop2 是一种细胞表面糖蛋白，在多种上皮性癌中过表达，在正常组织中表达水平较低或受到限制。Trop2 的表达与肿瘤侵袭性增加、转移和患者生存率降低有关，但 Trop2 介导的信号机制仍不清楚。在这里，我们研究了鼠 Trop2（mTrop2）对肿瘤细胞功能的影响，以及该癌基因激活的一些信号机制。
mTrop2 表达在低血清浓度下显著增加肿瘤细胞的增殖、迁移、集落形成和非锚定依赖性生长。这些体外特征转化为在皮下和原位胰腺癌小鼠模型中肿瘤生长的增加，并且还导致肝转移的增加。mTrop2 表达还通过增加 cyclin D1 和 cyclin E 的水平以及下调 p27 来增加磷酸化 ERK1/2 的水平，从而介导细胞周期进程，从而增加细胞周期进程。在过表达人 Trop2 的人胰腺导管上皮细胞和结直肠腺癌细胞中也观察到 ERK 的激活。
这些发现表明 mTrop2 表达对癌细胞的一些致病作用，以及靶向该细胞表面糖蛋白的重要性。本研究还首次表明 Trop2 激活的分子信号通路对癌细胞的生长和存活具有重要意义。
