{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:29:43Z","timestamp":1791286183932,"version":"4.1.0"},"reference-count":57,"publisher":"The Endocrine Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Context:<\/jats:title><jats:p>Somatic mutations in the Med12 gene are known to activate Wnt\/\u03b2-catenin signaling in human uterine fibroids (UFs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective:<\/jats:title><jats:p>The objective of the study was to examine the role of vitamin D3 in the modulation of Wnt\/\u03b2-catenin and mammalian target of rapamycin (mTOR) signaling in human UF cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design:<\/jats:title><jats:p>Immortalized human UF cells (HuLM) and human primary UF (PUF) cells were treated with increasing concentrations of vitamin D3 and thereafter analyzed using Western blots and immunocytochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcome Measures:<\/jats:title><jats:p>Wnt\/\u03b2-catenin and mTOR signaling proteins in cultured HuLM and PUF cells were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>UF tumors with Med12 somatic mutations showed an up-regulation of Wnt4 and \u03b2-catenin as compared with adjacent myometrium. Vitamin D3 administration reduced the levels of Wnt4 and \u03b2-catenin in both HuLM and PUF cells. Vitamin D3 also reduced the expression\/activation of mTOR signaling in both cell types. In contrast, vitamin D3 induced the expression of DNA damaged-induced transcription 4 (an inhibitor of mTOR) and tuberous sclerosis genes (TSC1\/2) in a concentration-dependent manner in HuLM cells. Furthermore, we observed a concentration-dependent reduction of Wisp1 (Wnt induced signaling protein 1) and flap endonuclease 1 proteins in HuLM cells. Additionally, abrogation of vitamin D receptor expression (by silencing) in normal myometrial cells induces Wnt4\/\u03b2-catenin as well as prompts a fibrotic process including an increase in cell proliferation and increased extracellular matrix production. Together these results suggest that vitamin D3 functions as an inhibitor of Wnt4\/\u03b2-catenin and mTOR signaling pathways, which may play major roles in fibroid pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion:<\/jats:title><jats:p>Vitamin D3 may have utility as a novel long-term therapeutic and\/or preventive option for uterine fibroids.<\/jats:p><\/jats:sec>","DOI":"10.1210\/jc.2015-3555","type":"journal-article","created":{"date-parts":[[2016,1,28]],"date-time":"2016-01-28T18:03:10Z","timestamp":1454004190000},"page":"1542-1551","source":"Crossref","is-referenced-by-count":83,"title":["Vitamin D3 Inhibits Wnt\/\u03b2-Catenin and mTOR Signaling Pathways in Human Uterine Fibroid Cells"],"prefix":"10.1210","volume":"101","author":[{"given":"Ayman","family":"Al-Hendy","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology (A.A.-H., M.P.D., S.K.H.), Georgia Regents University, Medical College of Georgia, Augusta, Georgia 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