Mol. Hum. Reprod. Advance Access originally published online on March 9, 2007
Molecular Human Reproduction 2007 13(5):323-332; doi:10.1093/molehr/gam005
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Altered expression of HOXA10 in endometriosis: potential role in decidualization
1 Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL, USA 2 Department of Obstetrics, Gynecology and Reproductive Sciences 3 Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA 4 Departments of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, IL, USA 5 Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
6 To whom correspondence should be addressed at: Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, 303 E. Superior St, Lurie 4-117, Chicago, IL 60611, USA. Tel.: 312 503 5377; Fax: 312 503 0095; E-mail: j-kim4{at}northwestern.edu
Endometriosis is a poorly understood gynaecologic disorder that is associated with infertility. In this study, we examined the expression of HOXA10 in the eutopic endometrium of baboons with induced endometriosis. A decrease in HOXA10 mRNA was observed after 3, 6, 12 and 16 months of disease, which reached statistical significance at 12 and 16 months. HOXA10 protein levels were decreased in both the epithelial and stromal cells of the endometrium. Furthermore, expression of ß3 integrin (ITGB3), which is upregulated by HOXA10, was decreased, whereas EMX2, a gene that is inhibited by HOXA10, was increased. Next, methylation patterns of the HOXA10 gene were analysed in the diseased and control animals. The F1 region on the promoter was found to be the most significantly methylated in the endometriosis animals and this may account for the decrease in HOXA10 expression. Finally, we demonstrate that stromal cells from the eutopic endometrium of baboons with endometriosis expressed significantly higher levels of insulin-like growth factor binding protein-1 (IGFBP1) mRNA than disease-free animals in response to estradiol, medroxyprogesterone acetate and dibutyryl cAMP (H + dbcAMP). The functional role of HOXA10 in IGFBP1 expression was further explored using human endometrial stromal cells (HSC). Overexpression of HOXA10 in HSC resulted in a decrease of IGFBP1 mRNA, whereas silencing HOXA10 caused an increase of IGFBP1 mRNA, even in the presence of H + dbcAMP. These data demonstrate that HOXA10 negatively influences IGFBP1 expression in decidualizing cells. Thus, the decrease in HOXA10 levels may in part be involved with the altered uterine environment associated with endometriosis.
Key words: decidualization/endometriosis/endometrium/HOXA10/uterus
Submitted on January 9, 2007; accepted on January 12, 2007.
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