Steroid hormone regulation of EMP2 expression and localization in the endometrium

Wadehra, Madhuri; Mainigi, Monica; Morales, Shawn A.; Rao, Rajiv G; Gordon, Lynn K.; Williams, Carmen J.; Braun, Jonathan

doi:10.1186/1477-7827-6-15

Cited by 27 publications

(18 citation statements)

References 21 publications

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“…Previous studies have suggested that EMP2 expression is regulated by progesterone (31). As progesterone increases EMP2 expression, we predicted that progesterone treatment may enhance the rate of anti-EMP2 diabody mediated apoptosis in RL95-2 cells as these cells express functional progesterone receptors (34, 35).…”

Section: Resultsmentioning

confidence: 99%

“…For hormone treatment, RL95-2 cells at 60–70% confluence were washed in PBS, and subsequently incubated with progesterone (Sigma., St. Louis, MO) in treatment medium (DMEM/Ham’s F-12 supplemented with 0.5% charcoal-stripped FBS (Omega Scientific, Tarzana, CA), 1% penicillin-streptomycin, and 1% L-glutamine). Progesterone was and added to treatment medium at 25 μM as previous described (31). Cell viability was determined by trypan blue exclusion.…”

Section: Methodsmentioning

confidence: 99%

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Diabodies Targeting Epithelial Membrane Protein 2 Reduce Tumorigenicity of Human Endometrial Cancer Cell Lines

Shimazaki

Lepin²,

Wei³

et al. 2008

Clinical Cancer Research

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Purpose Endometrial cancer (EC) is the most common gynecologic malignancy. One promising biomarker is epithelial membrane protein-2 (EMP2), and its expression is an independent prognostic indicator for tumors with poor clinical outcome expression. The present study assesses the suitability of EMP2 as a therapeutic target. Experimental Design Human monovalent anti-EMP2 antibody fragments were isolated from a human phage display library, and engineered as bivalent antibody fragments (diabodies) with specificity and avidity to both EMP2 peptides and native cell-surface EMP2 protein. Diabodies were assessed using cell death and apoptosis assays. In addition, the efficacy of EMP2 diabodies on EC tumors was determined using mouse xenograft models. Results Treatment of human endometrial adenocarcinoma cell lines with anti-EMP2 diabodies induced significant cell death and caspase 3 cleavage in vitro. These responses correlated with cellular EMP2 expression, and were augmented by progesterone (which physiologically induces EMP2 expression). In vivo, treatment of subcutaneous human xenografts of HEC-1A cell lines with anti-EMP2 diabodies suppressed tumor growth, and induced striking xenograft cell death. Conclusions These findings suggest that EMP2 may be a potential pharmacological target for human EC.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Diabodies Targeting Epithelial Membrane Protein 2 Reduce Tumorigenicity of Human Endometrial Cancer Cell Lines

Shimazaki

Lepin²,

Wei³

et al. 2008

Clinical Cancer Research

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“…In normal tissue, EMP2 has a discrete tissue distribution, with high expression in secretory endometrium (10, 11), lung alveolar epithelium (12), and in retinal pigmented epithelium within the eye (13). Dysregulation of EMP2 has been implicated in endometrial cancer, where EMP2 expression correlates with poor prognosis and survival (14), and EMP2 is the only known early diagnostic marker to predict endometrial hyperplasia progression to endometrial cancer (15).…”

Section: Introductionmentioning

confidence: 99%

Epithelial Membrane Protein-2 Is a Novel Therapeutic Target in Ovarian Cancer

Maresh²,

Soslow³

et al. 2010

Clinical Cancer Research

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Purpose: The tetraspan protein epithelial membrane protein-2 (EMP2) has been shown to regulate the surface display and signaling from select integrin pairs, and it was recently identified as a prognostic biomarker in human endometrial cancer. In this study, we assessed the role of EMP2 in human ovarian cancer.Experimental Design: We examined the expression of EMP2 within a population of women with ovarian cancer using tissue microarray assay technology. We evaluated the efficacy of EMP2-directed antibody therapy using a fully human recombinant bivalent antibody fragment (diabody) in vitro and ovarian cancer xenograft models in vivo.Results: EMP2 was found to be highly expressed in >70% of serous and endometrioid ovarian tumors compared with nonmalignant ovarian epithelium using a human ovarian cancer tissue microarray. Using anti-EMP2 diabody, we evaluated the in vitro response of nine human ovarian cancer cell lines with detectable EMP2 expression. Treatment of human ovarian cancer cell lines with anti-EMP2 diabodies induced cell death and retarded cell growth, and these response rates correlated with cellular EMP2 expression. We next assessed the effects of anti-EMP2 diabodies in mice bearing xenografts from the ovarian endometrioid carcinoma cell line OVCAR5. Anti-EMP2 diabodies significantly suppressed tumor growth and induced cell death in OVCAR5 xenografts.Conclusions: These findings indicate that EMP2 is expressed in the majority of ovarian tumors and may be a feasible target in vivo. Clin Cancer Res; 16(15); 3954-63. ©2010 AACR.

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“…Interestingly, another GAS3 family member EMP2 has been detected in the endometrium [25,28,41]. With regard to EMP2 and PMP22, a unique regulatory phenotype has been observed within endometrial cells.…”

Section: Discussionmentioning

confidence: 99%

Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium

Rao

Sudhakar

Hogue

et al. 2011

Reprod Biol Endocrinol

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BackgroundPMP22, a member of the GAS3 family of tetraspan proteins, is associated with a variety of neurological diseases. Previous studies have shown that PMP22 is expressed in proliferative endometrium, but its function within this tissue is poorly understood. In this study, we first characterized the expression of PMP22 in the human menstrual cycle and began to characterize its function in the endometrium.MethodsUsing a combination of immunohistochemistry and quantitative PCR, we characterized the expression of PMP22 in both proliferative and secretory endometrium. Differences in PMP22 expression between proliferative and secretory endometrium were determined using a Mann-Whitney U test. In order to investigate the influence of PMP22 on α6 integrin expression, cells were created that ectopically overexpressed PMP22 or expressed a siRNA to inhibit its expression. These cells were analyzed for changes in integrins and binding to extracellular matrices.ResultsIn this study, we show that PMP22 expression is higher in proliferative phase than secretory phase. Functionally, we have begun to characterize the functional significance of this expression. Previous studies have suggested a link between PMP22 and α6 integrin, and therefore we asked whether PMP22 could associate or potentially modulate the expression of α6 integrin. Expression of both PMP22 and α6 integrin were detectable in endometrial epithelial and stromal cells, and we show that both proteins can associate and colocalize with each other. To understand if PMP22 directly altered the expression of a6 integrin, we examined cell lines with modulated levels of the protein. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression.ConclusionThese findings suggest a physiologic role for PMP22 on the expression of α6 integrin. We predict that this may be important for the maintainence of endometrial integrity and to the disease biology associated with altered levels of α6 integrin expression in the endometrium.

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Steroid hormone regulation of EMP2 expression and localization in the endometrium

Abstract: These findings suggest that targeting of EMP2 to specific locations under the influence of these steroid hormones may be important for integrating the molecular responses required for implantation competence.

Cited by 27 publications

References 21 publications

Diabodies Targeting Epithelial Membrane Protein 2 Reduce Tumorigenicity of Human Endometrial Cancer Cell Lines

Diabodies Targeting Epithelial Membrane Protein 2 Reduce Tumorigenicity of Human Endometrial Cancer Cell Lines

Epithelial Membrane Protein-2 Is a Novel Therapeutic Target in Ovarian Cancer

Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium

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