Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway

Rafael Cubas,Changyi Chen,Sheng Zhang,Min Li,Qizhi Yao

doi:10.1186/1476-4598-9-253

Rafael Cubas, Changyi Chen + Show 3 more

Open Access

https://doi.org/10.1186/1476-4598-9-253

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Journal: Molecular Cancer	Publication Date: Sep 21, 2010
Citations: 199	License type: cc-by

Affiliation: Baylor College of Medicine

Abstract

BackgroundTrop2 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.ResultsmTrop2 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.ConclusionsThese 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.

Highlights

Trop2 is a cell-surface glycoprotein overexpressed by a variety of epithelial carcinomas with reported low to restricted expression in normal tissues
To obtain a more comprehensive understanding of the effect murine Trop2 (mTrop2) had on cell proliferation, we examined the cell cycle progression of Panc02, Panc02-GFP and Panc02-mTrop2 cells by propidium iodide staining and flow cytometry analysis
These results demonstrate that mTrop2 expression leads to increased cell growth by inducing a faster progression into the synthesis phase of the cell cycle

Summary

Introduction

Trop is a cell-surface glycoprotein overexpressed by a variety of epithelial carcinomas with reported low to restricted expression in normal tissues. Expression of Trop has been associated with increased tumor aggressiveness, metastasis and decreased patient survival, but the signaling mechanisms mediated by Trop are still unknown. Trop is highly conserved among species with a 79% identical amino acid composition between human and murine Trop2 This protein was initially found to be highly expressed in trophoblast cells, which arise from epithelial trophectoderm cells and become invasive, phagocytosing and displacing uterine epithelial cells. One study has shown the presence of a phosphatidylinositol 4,5-bis phosphate (PIP2)-binding sequence highly homologous to that of gelsolin [16] Within this sequence there is a conserved serine residue which is phosphorylated by protein kinase C (PKC) [17]. PKC and mitogen-activated protein kinases (MAPKs) including ERK1/2 may be involved in Trop induced tumor cell growth [17,18]

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