RC4.5 - ECE_2775 - The anti-Müllerian hormone suppresses uterine leiomyoma growth via a miR-181a-regulated molecular switch

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Abstract Uterine leiomyomas (ULs) are common, benign neoplasms, in women of reproductive age. ULs may cause severe anemia, after heavy menstrual bleeding, pelvic pain, infertility and significant morbidity, often necessitating invasive, surgical intervention. Despite their prevalence, the pathogenesis of ULs remains not fully elucidated, with roles for both hormonal and epigenetic factors, which modulate gene expression, through variations of micro-ribonucleic acids (miRNAs). Anti-Müllerian hormone (AMH) has been shown to be a potential suppressor of ULs, but its interactions with regulatory miRNAs, like miR-181a, is still unexplored in this context. In this study, we investigated the interplay between the AMH and miR-181a, in UL pathophysiology. The expression profiles of AMH, AMHRII, and miR-181a were characterized in UL tissue versus normal myometrium. The functional relationship and downstream molecular mechanisms were examined in UL cells, focusing on SMAD and PI3K/AKT/mTOR signaling pathways, along with cellular outcomes, like proliferation and senescence. We found that both AMH and its receptor, AMHRII, were overexpressed in ULs compared to normal myometrium, as was miR-181a. Functionally, AMH upregulated miR-181a expression in UL cells. This interaction induced a tumor-suppressive state, by activating the SMAD1/4 pathway, as well as the phosphorylation and nuclear translocation of SMAD1. Concurrently, AMH inhibited the pro-proliferative PI3K/AKT/mTOR axis, through PTEN upregulation and triggering cellular senescence. Notably, the absence of miR-181a reversed this effect of AMH, causing it to promote proliferation via the PI3K/AKT/mTOR pathway, by increasing the expression of pro-proliferative proteins, such as XIAP. Our results revealed that AMH and miR-181a maintain a homeostatic, growth-suppressive axis in ULs. Disruption of this balance, particularly miR-181a deficiency, can convert the role of AMH, from inhibitor to promoter of proliferation. A critical protective mechanism is shown in ULs, where AMH and miR-181a cooperate to inhibit growth. This positioned AMHRII signaling and the AMH/miR-181a axis as crucial therapeutic targets for non-surgically treating UL and other benign, Müllerian-related conditions.

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