Tissue factor is regulated by epidermal growth factor in normal and malignant human endometrial epithelial cells

Sumie Kato; Mauricio Pinto; Andrés Carvajal; Natalia Espinoza; Carolina Monsó; Loreto Bravo; Manuel Villalon; Mauricio Cuello; Andrew F. Quest; Akihiko Suenaga; Jan J. Brosens; Gareth I. Owen

doi:10.1160/TH05-01-0066

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(02): 444-453
DOI: 10.1160/TH05-01-0066

Cellular Proteolysis and Oncology

Schattauer GmbH

Tissue factor is regulated by epidermal growth factor in normal and malignant human endometrial epithelial cells

Authors

Sumie Kato

¹Departamento de Endocrinología, Facultad de Ciencias Biológicas

²Departamento de Obstetricia y Ginecologia, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
Mauricio Pinto

¹Departamento de Endocrinología, Facultad de Ciencias Biológicas
Andrés Carvajal

¹Departamento de Endocrinología, Facultad de Ciencias Biológicas
Natalia Espinoza

¹Departamento de Endocrinología, Facultad de Ciencias Biológicas
Carolina Monsó

¹Departamento de Endocrinología, Facultad de Ciencias Biológicas
Loreto Bravo

¹Departamento de Endocrinología, Facultad de Ciencias Biológicas
Manuel Villalon

¹Departamento de Endocrinología, Facultad de Ciencias Biológicas
Mauricio Cuello

²Departamento de Obstetricia y Ginecologia, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
Andrew F. Quest

³Centro FONDAP de Estudios Moleculares de la Celula (CEMC), Programa de Biologia Celular y Molecular, Universidad de Chile, Santiago, Chile
Akihiko Suenaga

⁴Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, United Kingdom
Jan J. Brosens

⁴Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, London, United Kingdom
Gareth I. Owen

¹Departamento de Endocrinología, Facultad de Ciencias Biológicas

Abstract

Summary

Tissue Factor (TF), the initiator of the extrinsic coagulation cascade, is overexpressed in a variety of cancers. TF is also expressed in normal human endometrium but little is known about its expression or regulation in endometrial cancer. We demonstrate herein that TF is expressed in the endometrial adenocarcinoma cell line Ishikawa. Furthermore, epidermal growth factor (EGF) induces a rapid and sustained increase in TF expression. Estradiol and progesterone had no effect on basal or EGF-induced TF expression in Ishikawa cells. In contrast to the pronounced and sustained upregulation at the protein level,EGF treatment elicited only a modest and transient increase in TF mRNA levels. This activity corresponded to the response observed from an exogenous TF promoter construct. However, the induction of TF was abrogated by cycloheximide as well as actinomycin-D, inhibitors or protein- and mRNA-synthesis, re-spectively, demonstrating that EGF mediates its effect through activation of the TF gene. Fractionation experiments showed that EGF increases TF presence in caveolin-1 containing membrane fractions. Coagulation and invasion assays were used to explore the physiological implications of TF regulation. The results demonstrate that EGF-mediated induction of TF increases the procoagulant activity and invasive potential of Ishikawa cells. Furthermore, immunocytochemistry confirmed that TF is regulated by EGF in primary cultures of normal endometrial epithelial cells and malignant tumor cells. In conclusion, EGF-mediated upregulation ofTF results in accumulation of this glycoprotein in caveolae-like membrane fractions and increased coagulative and invasive potential. Our results suggest that TF may play an integral role in endometrial carcinogenesis.

Keywords

Endometrium - Ishikawa - coagulation - invasion - caveolin

Full Text

References

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