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- Author: Meng-Hsing Wu x
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Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Endometriosis is a common gynecological disease in reproductive-age women. Although the hormone-dependent therapy is the first line treatment for endometriosis, it is not a curative regimen and associated with severe side-effects, which significantly decrease the life quality of affected individuals. To seek a target for treatment of endometriosis, we focused on plasma membrane proteins that are elevated in ectopic cells and exert beneficial effects in cell growth and survival. We performed bioinformatics analysis and identified the neurotrophic receptor tyrosine kinase 2 (NTRK2) as a potential candidate for treatment. The expression levels of NTRK2 were markedly upregulated in the lesions of clinical specimen as well as in the mouse endometriotic-like lesion. Mechanistic investigation demonstrated that upregulation of NTRK2 is induced by hypoxia in a hypoxia-inducible factor 1 alpha-dependent manner. Knockdown of NTRK2 or administration of ANA-12, a selective antagonist of NTRK2, significantly induced endometriotic stromal cells death, suggesting it may be a potential therapeutic agent. In vivo study using surgery-induced endometriosis mice model showed ANA-12 (1.5 mg/kg body weight) treatment induced apoptosis of endometriotic cells and caused the regression of ectopic lesions. Taken together, our findings suggest a possible mechanism responsible for the aberrant expression of NTRK2 in endometriotic lesions and this may be involved in the pathogenesis of endometriosis.
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Department of Obstetrics & Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Department of Physiology, National Cheng Kung University, Tainan, Taiwan
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Endometriosis is a benign gynecological disease that affects about 10% of women of reproductive age. Patients with endometriosis suffer from long-term coexistence with dysmenorrhea, dyspareunia, and even infertility, which severely reduces quality of life. So far, surgical removal and hormonal medication are the major treatment options; however, high recurrence and severe adverse effects hamper the therapeutic efficacy. Hypoxia is an inevitable cellular stress in many diseases that regulates the expression of a significant subset of genes involved in pathophysiological processes. A growing body of evidence demonstrates that hypoxia plays critical role in controlling the disease phenotypes of endometriosis, such as increasing adhesion ability, causing dysregulation of estrogen biosynthesis, aberrant production of proinflammatory cytokines, increasing angiogenic ability, and suppression of immune functions. In this review, we summarize the findings of the most recent studies in exploring the underlying mechanisms of hypoxia involved in endometriosis. Potential therapeutic options for targeting HIF and downstream effectors will also be discussed.
