The Cell-Free Expression of MiR200 Family Members Correlates with Estrogen Sensitivity in Human Epithelial Ovarian Cells.

Éva Márton,Lóránd Göczi,Alexandra Varga,Lajos Széles,András Penyige,Bálint Nagy,Melinda Szilágyi

doi:10.3390/ijms21249725

Abstract

Exposure to physiological estrogens or xenoestrogens (e.g., zearalenone or bisphenol A) increases the risk for cancer. However, little information is available on their significance in ovarian cancer. We present a comprehensive study on the effect of estradiol, zearalenone and bisphenol A on the phenotype, mRNA, intracellular and cell-free miRNA expression of human epithelial ovarian cell lines. Estrogens induced a comparable effect on the rate of cell proliferation and migration as well as on the expression of estrogen-responsive genes (GREB1, CA12, DEPTOR, RBBP8) in the estrogen receptor α (ERα)-expressing PEO1 cell line, which was not observable in the absence of this receptor (in A2780 cells). The basal intracellular and cell-free expression of miR200s and miR203a was higher in PEO1, which was accompanied with low ZEB1 and high E-cadherin expression. These miRNAs showed a rapid but intermittent upregulation in response to estrogens that was diminished by an ERα-specific antagonist. The role of ERα in the regulation of the MIR200B-MIR200A-MIR429 locus was further supported by publicly available ChIP-seq data. MiRNA expression of cell lysates correlated well with cell-free miRNA expression. We conclude that cell-free miR200s might be promising biomarkers to assess estrogen sensitivity of ovarian cells.

Highlights

Cancer is the second leading cause of death worldwide
In our previous studies we identified several cell-free miRNAs that are over-represented in the plasma samples of patients with ovarian carcinoma compared to healthy controls [24,25]
We show that estrogens and estrogen receptor α (ERα) affect the expression of intracellular and cell-free counterparts of miR200 family members and miR203a, which have an influence on E-cadherin expression and the migratory ability of PEO1 and A2780 cells

Summary

Introduction

Cancer is the second leading cause of death worldwide. Among women, ovarian cancer is considered to be the fifth most common cause of cancer death and it is the most lethal form of gynecological malignancy [1]. Xenoestrogens can be defined as chemicals that mimic the effect of physiological estrogens They can be divided into natural compounds (e.g., produced by fungi, such as mycoestrogens e.g., zeralaenone, ZEA) and synthetic agents (e.g., bisphenol A, BPA). BPA tends to leach from plastic items, human contamination is considered to be high especially in industrialized countries, which is supported by the observation that BPA has been detected in human serum, urine, amniotic fluid and breast milk [9,10] Both ZEA and BPA are confirmed to have an estrogen-disruptive effect in domestic animals and humans and their toxicity is suggested by several studies [9,10,11,12,13]

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