Molecular Mechanisms of Stress-Induced Phosphoprotein 1 (STIP1) and Its Therapeutic Potential in Endometriosis

Endometriosis is an important gynecological disease, which affects about 6 to 10% of women of reproductive age. In women with infertility, the prevalence rate is approaching 30%. Endometriosis often causes pain, and it can be detected in up to 50% of women with severe dysmenorrhea or pelvic pain. Several types of pain are associated with endometriosis, such as dyemenorrhea, deep dyspareunia, dyschezia (pelvic pain with defecation), and chronic pelvic pain. Main goals of endometriosis treatment include to improve fertility and to control pain. The majority of current therapeutic strategies for endometriosis aim at modification of hormone status and/or anti-inflammation to offset the hyperestrogenic, inflammatory nature of the disease. The strategy of direct targeting endometriosis itself, however, is lacking. Stress-induced phosphoprotein 1 (STIP1, GeneID 10963; HPRD 05454) is a 62.6 kDa protein, also known as heat shock protein (HSP)-organizing protein (HOP). In addition to modulation of the chaperone activity of HSP 90 and HSP 70, STIP1 has been involved in many functions. However, the association between STIP1 and endometriosis has been reported only by our group. The stimulatory roles of STIP1 in endometriosis are supported by its elevated serum levels in patients with endometriosis and its high expression in endometriotic tissues. The granting of a US Patent 7851230 (Stress-induced phosphoprotein 1 as a biomarker for the detection of human ovarian cancers and endometriosis.) to us has not only justified the novelty of such findings, but also discouraged our international competitors from doing similar research in endometriosis. Matrix metalloproteinase-9 (MMP-9) and signal transducers and activators of transcription 3 (STAT3) have been implicated in the pathogenesis of endometriosis. Our preliminary results that STIP1 knockdown led to suppression of MMP-9 and inhibition of STAT3 phosphorylation firmly support our working hypotheses that STIP1 plays roles in pathogenesis of endometriosis by regulating the functions of MMP-9 and STAT3. Our broad objective of this study is to understand the role of STIP1 in the pathogenesis of endometriosis. Through increasing our understanding of its molecular mechanisms, we may develop novel therapeutic strategies for endometriosis by targeting STIP1. In this three-year project, we attempt to achieve three Specific Aims: to delineate the function of MMP9 and its regulation by STIP1 in endometriosis, to identify the function of STAT3 and its regulation by STIP1 in endometriosis, and to develop targeted therapy of endometriosis by aiming at STIP1.

Project ID:PC10501-1648
External Project ID:MOST103-2314-B182-057-MY3