Abstract
Endometrial cancer is the most common gynecologic malignancy diagnosed among women in developed countries. One recent biomarker strongly associated with disease progression and survival is epithelial membrane protein-2 (EMP2), a tetraspan protein known to associate with and modify surface expression of certain integrin isoforms. In this study, we show using a xenograft model system that EMP2 expression is necessary for efficient endometrial tumor formation, and we have started to characterize the mechanism by which EMP2 contributes to this malignant phenotype. In endometrial cancer cells, the focal adhesion kinase (FAK)/Src pathway appears to regulate migration as measured through wound healing assays. Manipulation of EMP2 levels in endometrial cancer cells regulates the phosphorylation of FAK and Src, and promotes their distribution into lipid raft domains. Notably, cells with low levels of EMP2 fail to migrate and poorly form tumors in vivo. These findings reveal the pivotal role of EMP2 in endometrial cancer carcinogenesis, and suggest that the association of elevated EMP2 levels with endometrial cancer prognosis may be causally linked to its effect on integrin-mediated signaling.
Highlights
Endometrial cancer is a significant disease in women with nearly one out of every thirty-five women developing the disease over her lifetime [1,2]
Hemotoxylin and eosin staining confirmed the size of the tumors, where HEC-1A/RIBO tumors were significantly smaller than HEC-1A/epithelial membrane protein-2 (EMP2) and HEC-1A/V tumors
We examine the tumor growth of endometrial carcinoma cells with increased or reduced EMP2 expression to determine the contribution of EMP2 to endometrial cancer tumorigenicity
Summary
Endometrial cancer is a significant disease in women with nearly one out of every thirty-five women developing the disease over her lifetime [1,2]. In the United States endometrial cancer is the most common malignancy of the female genital tract. One protein associated with the development of endometrial cancer is epithelial membrane protein-2 (EMP2). EMP2 is a member of the GAS-3/PMP22 subfamily, which together with tetraspanins and connexins, comprise the three subfamilies of the large 4-transmembrane family. EMP2 functions as a prognostic marker which can help predict patients who will progress from endometrial hyperplasia to cancer [4]. In patients with endometrial cancer, EMP2 positive tumors have been shown to be more aggressive and invasive, and its expression within tumors correlates with poor prognosis and survival [4,5]
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