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

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.

Common Cervicovaginal Microbial Supernatants Alter Cervical Epithelial Function: Mechanisms by Which Lactobacillus crispatus Contributes to Cervical Health

“…The cervix has several critical functions including (1) maintenance of the integrity of the cervical epithelial barrier that lines the cervical lumen and acts to prevent microbial invasion and infection and (2) appropriate timing of cervical remodeling to prepare for delivery. Previous studies by our group and others have shown that many factors can promote a breakdown in the cervical epithelial barrier and initiate cervical remodeling through alterations in inflammation and infection ( Nold et al, 2012 ), microRNAs (miRNAs) ( Anton et al, 2017 ), biomechanical properties of the cervix ( Yoshida et al, 2016 ; Barnum et al, 2017 ), and the CV metabolome ( Ghartey et al, 2015 , 2017 ) and microbiome ( Romero et al, 2014a ; Stout et al, 2017 ). Differentially expressed miRNAs in the CV space are associated with PTB ( Elovitz et al, 2014 ), short gestation ( Sanders et al, 2015 ), and disruption of the cervical epithelial barrier ( Anton et al, 2017 ).…”

The Microrna-143/145 Cluster in Tumors: A Matter of Where and When

“…Finally, proteins involved in cell-cell adhesion and cell motility can be targeted by both microRNAs. For example, the cell-cell adhesion protein JAM-A [102] and the actin bundling protein FSCN1 [55,72,[102][103][104][105] have both been described as miR-145 targets, suggesting inhibition of cell adhesion and movement. Indeed, overexpression of miR-145 in breast cancer cell lines decreased actin stress fibers, and miR-143 was shown to regulate ADDUCIN 3 [106] and FIBRONECTIN [21,49], leading to reduced cell migration.…”

Down-regulated miR-145 rescues insulin resistance in endothelial cells

“…In cancer cells, Chen Z et al showed that miR-145 over-expression decreased the proliferation of prostate cancer cells and promoted cell apoptosis [32]. Anton L et al [33] also found that transfection of miR-145 could restrain cervical cell multiplication through increasing apoptosis and blocking cell cycle. In brief, these studies indicated that the over-expression of miR-145 expedited apoptosis in cells of various diseases, which may be a potential target for the treatment of some diseases.…”