Profilin-1 is dysregulated in endometroid (type I) endometrial cancer promoting cell proliferation and inhibiting pro-inflammatory cytokine production.

Endometrial cancer (EC) is the most common gynaecological malignancy. Alarmingly its incidence and mortality rate is increasing particularly in younger women of reproductive age. Despite this, there are limited treatment options for EC. Profilin-1 (PFN1) regulates tumorigenesis in numerous cancers, but the role of PFN1 in EC has not been investigated. We hypothesized that PFN1 would have altered expression in EC and contribute to the development of EC. We quantified PFN1 in type 1 EC and benign/normal endometrium by RT-qPCR and IHC. The effect of silencing PFN1 on cell adhesion and proliferation was investigated using 2 EC cell lines (HEC1A and AN3CA). The effect of recombinant PFN1 (100 µM) on pro-inflammatory cytokine gene expression was investigated using THP1 monocyte cell line. PFN1 immunolocalized to glandular epithelial cells, vascular endothelial cells and leukocytes in the stromal compartment of normal endometrium and EC. PFN1 immunostaining intensity was significantly elevated in grade (G)I EC compared to normal endometrium, GI-II and GIII EC. In endometrial epithelial cancer cells alone, PFN1 immunostaining intensity was significantly reduced in GII and III EC compared to normal endometrium and GI EC. The stromal compartment of EC had strong PFN1 expression compared to benign and normal endometrium. Silencing PFN1 in the AN3CA endometrial epithelial cancer cell line significantly enhanced cell adhesion and proliferation. PFN1 treatment significantly down-regulated TNFα and IL1ß mRNA expression by THP1 cells. This study demonstrated that whilst PFN1 production is retained in the stromal compartment of EC, PFN1 production is lost in endometrial epithelial cancer cells with increasing cancer grade. PFN1 may play a role in the tumorigenesis of EC. Loss of PFN1 in GII and GIII endometrial epithelial cancer cells associated with sustained PFN1 by infiltrating immune cells may promote EC tumorigenesis due to increased endometrial epithelial cancer cell proliferation coupled with a pro-tolerance tumor microenvironment.

Human Blastocyst Secreted microRNA Regulate Endometrial Epithelial Cell Adhesion.

Successful embryo implantation requires synchronous development and communication between the blastocyst and the endometrium, however the mechanisms of communication in humans are virtually unknown. Recent studies have revealed that microRNAs (miRs) are present in bodily fluids and secreted by cells in culture. We have identified that human blastocysts differentially secrete miRs in a pattern associated with their implantation outcome. miR-661 was the most highly expressed miR in blastocyst culture media (BCM) from blastocysts that failed to implant (non-implanted) compared to blastocysts that implanted (implanted). Our results indicate a possible role for Argonaute 1 in the transport of miR-661 in non-implanted BCM and taken up by primary human endometrial epithelial cells (HEECs). miR-661 uptake by HEEC reduced trophoblast cell line spheroid attachment to HEEC via PVRL1. Our results suggest that human blastocysts alter the endometrial epithelial adhesion, the initiating event of implantation, via the secretion of miR, abnormalities in which result in implantation failure.