Direct Regulation of β3-Integrin Subunit Gene Expression by HOXA10 in Endometrial Cells

Abstract

Estrogen and progesterone regulate HOXA10 expression in the endometrium, where HOXA10 is necessary for implantation. The integrins are also involved in early embryo-endometrial interactions. Here we show that HOXA10 directly regulates beta3-integrin subunit expression in the endometrium, likely mediating the effect of sex steroids on beta3-integrin expression. beta3-Integrin expression was decreased in endometrium shown to have low HOXA10 expression. beta3-Integrin mRNA levels were increased in endometrial adenocarcinoma cells (Ishikawa) transfected with pcDNA3.1/HOXA10, and decreased in cells treated with HOXA10 antisense. Seven consensus HOXA10 binding sites were identified 5' of the beta3-integrin gene. Direct binding of HOXA10 protein to four sites was demonstrated by EMSA. Reporter gene expression increased in BT-20 cells cotransfected with pcDNA3.1/ HOXA10 and pGL3-promoter vector containing region F (encompassing all seven HOXA10 consensus sites). A 41-bp segment (Region A) showed highest affinity binding to HOXA10 protein. Increased reporter expression, equal in magnitude to that obtained with Region F, was obtained with Region A. HOXA10 protein binding within Region A was localized by deoxyribonuclease I footprinting. beta3-Integrin expression was directly up-regulated by HOXA10 through a 41-bp 5'-regulatory element. Sex steroids regulate the expression of endometrial beta3-integrin through a pathway involving HOXA10.

Identification of a HoxA10 Activation Domain Necessary for Transcription of the Gene Encoding β3 Integrin during Myeloid Differentiation

“…These studies identified a region of the ITGB3 promoter that interacts in vitro with the homeodomain transcription factor HoxA10. In these studies, overexpressed HoxA10 activated an artificial promoter construct with this region of the ITGB3 promoter in transfection experiments with a breast cancer cell line (10). Because HoxA10 is expressed in differentiating myeloid cells, the first hypothesis of our current studies was that HoxA10 regulates ITGB3 transcription during myelopoiesis.…”

“…However, regulation of ITGB3 transcription during myelopoiesis or in mature myeloid cells has not been studied. Indeed, the only previous studies of the ITGB3 promoter were performed in epithelial carcinoma cells (10). These studies identified a region of the ITGB3 promoter that interacts in vitro with the homeodomain transcription factor HoxA10.…”

A Novel Variant of HOXA10 gene, Ser19Cys, among Patients with Endometriosis and its Relationship with the Severity of the Disease

“…Its expression is regulated by estrogen and progesterone (Daftary et al, 2002). Progesterone and estrogen regulate expression of HOXA10 in the endometrium, through the progesterone receptor (PR) and estrogen receptor (ER).…”

“…HOXA10 is required for the implantation process, directly acts to regulate cell adhesion molecules (CAM) such as ITGAVB3 (Taylor et al, 1999;Daftary et al, 2002). HOXA10 expression in the endometrium has increased during ovulation (Bagot et al, 2000).…”

“…A slight decrease of HOXA10 expression is seen in luminal area, glands, and endothelium, but is reduced signifi cantly in the area of endometrial stromal endometriosis (Gui et al, 1999;Wu et al, 2005;Matsuzaki et al, 2009). HOXA10 expression decreases in the endometrium's endometriosis and followed by a defect in the expression of the target of HOXA10 gene such as EMX-2 and B3 integrin (Bagot et al, 2000;Daftary et al, 2002).…”