MiR-143 and miR-145 disrupt the cervical epithelial barrier through dysregulation of cell adhesion, apoptosis and proliferation

Lauren Anton,Amy G Brown,Ann Devine,Luz-Jeannette Sierra,Michal A Elovitz

doi:10.1038/s41598-017-03217-7

Lauren Anton, Amy G Brown + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-03217-7

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Journal: Scientific Reports	Publication Date: Jun 8, 2017
Citations: 39	License type: open-access

Affiliation: University of Pennsylvania

Abstract

Molecular mechanisms regulating preterm birth (PTB)-associated cervical remodeling remain unclear. Prior work demonstrated an altered miRNA profile, with significant increases in miR-143 and miR-145, in cervical cells of women destined to have a PTB. The study objective was to determine the effect of miR-143 and miR-145 on the cervical epithelial barrier and to elucidate the mechanisms by which these miRNAs modify cervical epithelial cell function. Ectocervical and endocervical cells transfected with miR-negative control, miR-143 or miR-145 were used in cell permeability and flow cytometry assays for apoptosis and proliferation. miR-143 and miR-145 target genes associated with cell adhesion, apoptosis and proliferation were measured. Epithelial cell permeability was increased in miR-143 and miR-145 transfected cervical epithelial cells. Cell adhesion genes, JAM-A and FSCN1, were downregulated with overexpression of miR-143 and miR-145. miR-143 and miR-145 transfection decreased cervical cell number by increasing apoptosis and decreasing cell proliferation through initiation of cell cycle arrest. Apoptosis genes, BCL2 and BIRC5, and proliferation genes, CDK1 and CCND2, were repressed by miR-143 and miR-145. These findings suggest that miR-143 and miR-145 play a significant role in cervical epithelial barrier breakdown through diverse mechanisms and could contribute to premature cervical remodeling associated with PTB.

Highlights

In the United States in 2015, 9.6 percent of all live births were delivered preterm[1]
We hypothesize that increased expression of miR-143 and miR-145 disrupts the integrity of the cervical epithelial barrier through regulation of cell adhesion, apoptosis and cell proliferation which initiates premature cervical remodeling resulting in early delivery
Ectocervical (Fig. 1a) and endocervical (Fig. 1b) cells transfected with miR-143 (n = 3, ecto: p = 0.0016, endo: p < 0.0001) and miR-145 (n = 3, ecto: p = 0.0003, endo: p = 0.0004) had a significant increase in epithelial cell permeability as evidenced by a significant increase in the amount of miR-143 JAM-A FSCN1 B-cell lymphoma 2 (BCL2) BIRC5 cyclin dependent kinase 1 (CDK1) cyclin D2 (CCND2)

Summary

Introduction

In the United States in 2015, 9.6 percent of all live births were delivered preterm[1]. The increased expression of miR-143 and miR-145 in cervical cells from women destined for a preterm birth suggested that these miRNAs have the ability to contribute significantly to cervical remodeling. We investigated the effects of miR-143 and miR-145 on cervical epithelial cell permeability to determine if these miRNAs have the ability to alter the cervical epithelial cell barrier. We focused on the molecular mechanisms contributing to the breakdown of the cervical epithelial cell barrier by investigating the effects of increased miR-143 and miR-145 expression on cell adhesion and growth. We hypothesize that increased expression of miR-143 and miR-145 disrupts the integrity of the cervical epithelial barrier through regulation of cell adhesion, apoptosis and cell proliferation which initiates premature cervical remodeling resulting in early delivery

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Conclusion