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

Lisanne George, Amy Winship, Kelli Sorby, Evdokia Dimitriadis, Ellen Menkhorst

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 IL1β 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.

Original languageEnglish
Number of pages6
JournalBiochemical and Biophysical Research Communications
DOIs
Publication statusAccepted/In press - 14 Aug 2020

Keywords

  • AN3CA
  • Profilin-1
  • THP1
  • Type 1 endometrial cancer

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