Effects of combined progesterone and 17β-estradiol treatment on the transcriptome of cultured human myometrial smooth muscle cells

Abstract

Chandran S, Cairns MT, O'Brien M, O'Connell E, Mashayekhi K, Smith TJ. Effects of combined progesterone and 17␤-estradiol treatment on the transcriptome of cultured human myometrial smooth muscle cells. Physiol Genomics 48: 50 -61, 2016. First published November 3, 2015 doi:10.1152/physiolgenomics.00021.2015.-A transcriptomic analysis of cultured human uterine smooth muscle cells (hUtSMCs) was performed to examine gene expression profiles in smooth muscle in an environment containing the two major steroid hormones that regulate the human myometrium in physiological states associated with estrous, pregnancy, labor, and pathophysiological states such as leiomyoma and endometrial cancer. hUtSMCs were treated with progesterone (P4) and 17␤-estradiol (E2) individually and in combination, in the presence and absence of RU486 (mifepristone). Transcription of many genes was modulated in the presence of P4 or E2 alone, but almost six times more genes were transcriptionally modulated in the presence of the P4/E2 hormone combination. In total 796 annotated genes were significantly differentially expressed in the presence of both P4 and E2 relative to their expression in untreated cells. Functional withdrawal of P4 by addition of RU486 effectively reversed almost all transcriptional changes caused by P4/E2 treatment. Gene ontology analysis of differentially expressed genes revealed a strong association between P4/E2 treatment and downregulated expression of genes involved in cell communication, signal transduction, channel activity, inflammatory response, and differentiation. Upregulated processes included cell survival, gene transcription, steroid hormone biosynthesis, muscle development, insulin receptor signaling, and cell growth.progesterone; 17␤-estradiol; uterine smooth muscle cells; microarray; transcriptomics THE TWO STEROID HORMONES, estrogen and progesterone (P4), play vital roles in maintaining pregnancy and initiating labor (51) and more generally in myometrial physiology and contractility. P4 maintains uterine quiescence during pregnancy, while estrogen induces uterine contraction at labor (49 -51). These hormones fluctuate relative to each other throughout life from puberty, through the fertile years, to the postfertile years and also within these life stages during specific physiological states such as estrous, pregnancy, labor, and menopause. Furthermore, both hormones have profound effects on pathophysiological conditions such as leiomyoma, endometriosis, and endometrial cancer.In maternal physiology these hormones induce changes that prepare the mother for pregnancy and aid in conceptus development (11). In most species, a sharp decline in circulating P4 and an increase in estrogen are observed toward parturition (11,38). However, in humans, no marked difference in the levels of circulating P4 or estrogen is noted before or at term (51). Hence, in humans, withdrawal of P4 and responsiveness of the myometrium to circulating estrogen during labor is believed to occur at a functional level, with changes in ho...

The study of progesterone action in human myometrial explants

“…One study comparing non-pregnant myometrium at t ¼ 0 to matched primary cell culture reported changes in expression of more than 1000 genes (Zaitseva et al, 2006) supporting our finding of marked changes in gene expression in primary cell culture systems. Some gene expression studies focused on gene expression in myometrial explants (Cordeaux et al, 2010) or cultured myometrial cells (Lei et al, 2015b;Chandran et al, 2016) in the presence or the absence of progestins and hence cannot be compared with our study. Other authors (Rehman et al, 2003;Bollapragada et al, 2009;Mittal et al, 2010;Chan et al, 2014) have sought to compare the gene expression profile of myometrium from non-labouring and labouring patients.…”

Modern Myoma Treatment in the Last 20 Years: A Review of the Literature

“…Increasingly, new insights into the molecular biological effects of hormones on leiomyoma cells are being investigated; however, so far no direct therapeutic consequences have emerged. [ 9 , 10 ].…”

XPG is Modulated by miR-4715-3p and rs873601 Genotypes in Lung Cancer

“…4,16 Genetic variants and posttranscriptional regulation alter functional motifs, and alterations in functional motifs may reduce DNA repair capacity and lead to increased cancer risks. 17,18 Our results revealed that miR-4715-3p modulated XPG expression and may have altered its repair ability, resulting in lung cancer [Supplementary Figure 2].…”