Regulated expression of aggrecanases of ADAMTS family in endometrial physiology and pathology

The ADAMTS (A Disintegrin and Metalloproteinase with TromboSpondin Repeats) are a novel family of secreted metalloproteinases. There is increasing evidence that distinct ADAMTS subtypes play key roles in embryonic development, reproduction and cancer. Nineteen ADAMTS subtypes have been identified in humans but most of them have been characterized only at the structural level. ADAMTS-1, -4, -5, -8, -9 and -15 have been subclassified into a subfamily, known as aggrecanases, owing to their ability to cleave the important extracellular matrix components, versican and aggrecan. Previous studies have determined that ADAMTS-1 and -5 are expressed in first trimester decidual cells and are regulated by IL-1ß and TGF- ß1. I have now found that gonadal steroids have complex regulatory effects upon ADAMTS-1 mRNA and ADAMTS-1 levels in endometrial stromal cells during the human menstrual cycle. I further demonstrate that progesterone (P4) and 5α-dihydrotestosterone (DHT), differentially regulated ADAMTS-5, -8, and -9 mRNA and protein levels in human endometrial stromal cells, suggesting that aggrecanases contribute to steroid-mediated ECM remodeling in the endometrium in preparation for pregnancy. My loss- and gain- of function studies have confirmed a function for ADAMTS-1 in endometrial cancer invasion. Overexpression of ADAMTS-1 in well-differentiated ECC-1 endometrial carcinoma cells promoted cell invasion. In contrast, siRNA-mediated silencing of endogenous ADAMTS-1 in poorly differentiated KLE cells decreased their invasive capacity. I have also found that 17ß-estradiol (E2) can up-regulate ADAMTS-1 mRNA and protein levels in ECC-1 cells. This suggests that ADAMTS-1 plays an important role in endometrial cancer progression, and that E2 promotes well-differentiated endometrial cancer cell invasion, at least in part by specific up-regulating ADAMTS-1 expression. Overall, my research provides useful insight into the molecular mechanisms that regulate endometrial physiology and pathology, and additional support for the concept that ADAMTS represent potentially useful prognostic biomarkers of recurrent pregnancy loss and endometrial cancer.Medicine, Faculty ofObstetrics and Gynaecology, Department ofGraduat