Expression of erythropoietin messenger ribonucleic acid in wild-type MED12 uterine leiomyomas under estrogenic influence: new insights into related growth disparities

Abstract

Objective: To determine factors that impact erythropoietin (EPO) production in leiomyomas. We have previously implicated EPO production in promoting the growth of some leiomyomas. Design: The relationship between EPO messenger RNA (mRNA) expression and MED12 gene mutations or mRNA expression levels of high-mobility group AT-hook (HMGA) 1 and HMGA2 were analyzed. Effects of 10 À8 M 17b-E 2 on EPO mRNA expression were evaluated using leiomyoma cells grown in primary cultures. Setting: Graduate school of medicine. Patient(s): Patients with leiomyoma. Intervention(s): We used tissue samples and clinical data of 108 patients with leiomyomas to analyze the relation between EPO mRNA expression and MED12 mutation. Tissue samples from another 10 patients with leiomyomas were collected for in vitro experimentation using primary cultures of leiomyoma and myometrial cells. Main Outcome Measure(s): Relations between EPO mRNA expression, MED12 exon 2 mutation, and HMGA1/HMGA2 mRNA expression levels in leiomyoma samplings, in addition to effects of estrogen (E) on EPO mRNA expression in cultures of leiomyoma cells. Result(s): The EPO mRNA level was threefold higher in leiomyomas with wild-type (vs. mutated) MED12 genes. There was no correlation between EPO and HMGA1 or HMGA2 mRNA expression levels. In wild-type MED12 leiomyomas only, E 2 treatment produced a twofold increase in EPO mRNA expression, whereas mutated MED12 leiomyomas were unaffected. Conclusion(s):The EPO mRNA expression increased significantly after E 2 treatment only in leiomyomas lacking MED12 mutations. In conjunction with prior evidence linking EPO mRNA expression levels and tumor size, E 2 -stimulated EPO mRNA expression may explain the marked growth disparities seen in these tumors. (Fertil Steril Ò 2019;111:178-85. Ó2018 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.

Growth disparities in uterine leiomyomas associated with MED12 mutation

“…Patients with MED12 mutations reportedly tend to develop multiple and smaller-sized tumors. In line with this, a recent study (2) demonstrated that leiomyomas without MED12 mutation were comparatively larger in size than those with MED12 mutation. This finding could explain why some uterine leiomyomas present an accelerated growth rate that often provokes patients to undergo medical intervention, whereas others might grow slowly or remain unchanged indefinitely.…”

“…In the context of uterine leiomyoma, MED12-linked mutations disrupt its direct interaction with components of the CDK8 and results in suppression of E-induced transcription and diminished cell growth (3). Considering that EPO production is regulated by E, the suppression of E-induced transcription, as observed in the study by Asano et al (2) in response to E. These findings provide clarity for why the lack of MED12 mutation is correlated with accelerated growth in certain leiomyomas, in that elevated transcription of EPO is induced by E. Thus, new treatments inhibiting EPO expression might be considered as a therapy to prevent the growth in uterine leiomyomas lacking MED12 mutation.…”

“…At the molecular level, one study (2) reported that erythropoietin (EPO) is sometimes detected at higher levels in uterine leiomyoma compared with the surrounding myometrium, and EPO messenger RNA levels appear to correlate with tumor progression and size. Considering that EPO is an important hormone involved not only in hematopoietic activity, but also in cell differentiation, control of apoptosis, angiogenesis, and/or vasculogenesis, EPO expression may affect the growth patterns of leiomyoma.…”

HMGA2 involvement in uterine leiomyomas development through angiogenesis activation

“…However, MED12mutated UL are characterized as vascular-poor and slowgrowing tumors. In this regard, it has been reported that erythropoietin (EPO), an important hormone involved in hematopoietic activity, cell differentiation, apoptosis control, angiogenesis, and/or vasculogenesis, was decreased in MED12-mutated ULs under estrogenic influence (5). Mutations in MED12 result in the disruption of mediator kinase activity and, consequently, alter CDK8 function, resulting in suppression of estrogen-induced transcription and diminished cell growth.…”

“…Mutations in MED12 result in the disruption of mediator kinase activity and, consequently, alter CDK8 function, resulting in suppression of estrogen-induced transcription and diminished cell growth. Because EPO production is regulated by estrogen, the inhibition of estrogen-induced transcription in MED12-mutated ULs could explain the decreased EPO expression levels in response to estrogen in these ULs, suggesting that it may be the reason why these tumors tend to be generally smaller than leiomyomas without MED12 mutation (5).…”