Molecular Human Reproduction

Overexpression of high affinity Type I adenosine receptors promotes the growth of uterine leiomyomas

Abstract Leiomyomas are benign proliferations of uterine smooth muscle found in 60% of women. A spatial redistribution of ecto-5'-nucleotidase (CD73, NT5E) that results in reduced extracellular concentrations of adenosine has recently been described in leiomyomas. However, the mechanisms by which altered extracellular adenosine levels contribute to leiomyoma growth remain poorly understood. To address this deficiency, a series of tissue specimens and primary cultures generated from matched specimens of myometrium and leiomyoma were used. Overexpression of Type 1 adenosine receptors (ADORA1) was observed when matched specimens and primary cultures were interrogated by RT-qPCR and western blot. By immunohistochemistry, ADORA1 expression was diffusely observed in myocytes in the leiomyoma complex, with only limited expression in vascular and other structures. Overexpression of ADORA1 was also observed in fibroblasts and multiple smooth muscle subtypes in the leiomyoma complex when single-cell transcriptomics data were interrogated. Incubation with N6-cyclopentyladenosine (CPA), a selective ADORA1 agonist, resulted in decreased proliferation of primary leiomyoma cultures, accompanied by decreased intracellular cAMP and enhanced cyclin D1 and phospho-AKT1 expression. To confirm the specificity of this observation, ADORA1 expression was directly targeted by siRNA, resulting in decreased proliferation, increased intracellular cAMP, and lower levels of cyclin D1 and phospho-AKT1. Collectively, these data indicate that overexpression of the ADORA1 receptor is a robust feature of uterine leiomyomas, where its activation by residual levels of extracellular adenosine potentially contributes to tumor growth by regulating AKT1-mediated signaling.

Racial disparity in uterine leiomyoma: new insights of genetic and environmental burden in myometrial cells

Abstract Uterine leiomyoma (LM), also known as uterine fibroids, are common gynecological tumors and can reach a prevalence of 70% among women by the age of 50 years. Notably, the LM burden is much higher in Black women with earlier onset, a greater tumor number, size, and severity compared to White women. Published knowledge shows that there are genetic, environmental, and lifestyle-based risk factors associated with racial disparity for LM. Significant strides have been made on genomic, epigenomic, and transcriptomic data levels in Black and White women to elucidate the underlying pathomolecular reasons of racial disparity in LM development. However, racial disparity of LM remains a major area of concern in gynecological research. This review highlights risk factors of LM and their role in different races. Furthermore, we discuss the genetics and uterine myometrial microenvironment in LM development. Comparative findings revealed that a major racial difference in the disease is linked to myometrial oxidative burden and altered ROS pathways which is relevant to the oxidized guanine in genomic DNA and MED12 mutations that drive the LM genesis. Considering the burden and morbidity of LM, we anticipate that this review on genetic risk and myometrial microenvironment will strengthen understanding and propel the growth of research to address the racial disparity of LM burden.