SLUG/HIF1-α/miR-221 regulatory circuit in endometrial cancer

The pathogenesis of endometrial cancer (EC) involves many regulatory pathways including transcriptional regulatory networks supported by transcription factors and microRNAs only in part known. The aim of this retrospective study was to explore the possible correlation in the EC microenvironment between master regulators of complex phenomena such as steroid responsiveness through estrogen receptor alpha (ERα) and progesterone receptor (PR), epithelial-to-mesenchymal transition (supported by SLUG transcription factor), hypoxia (with hypoxia inducible factor-1 alpha, HIF-1α), and obesity that has been recognized as a EC risk factor.

Formalin-Fixed Paraffin-Embedded (FFPE) blocks from University of Ferrara Pathology Archive were used and allocated into 2 groups according to their immunohistochemical positivity to ERα and PR, distinguishing the samples with a more benign prognosis (ERα⁺/PR⁺) from those with a poorer prognosis (ERα^-/PR^-). Immunohistochemistry for HIF1-α and SLUG was also performed. Body mass index (BMI) was registered at the time of diagnosis: patients with BMI ≥ 30 kg/m² were defined obese (OB). Total RNA was isolated for miR-221 analysis.

We showed a comparable percentage of HIF1-α and SLUG positive samples in the ERα⁺/PR⁺ and ERα^-/PR^- groups. However, the obesity factor impacted more in the ERα⁺/PR⁺ group since the ratio between OB and non-obese (NOB) patients with high expression of HIF1-α and SLUG was higher in ERα⁺/PR⁺ than in the ERα^-/PR^- group. miR-221 levels were significantly higher in the OB than NOB patients, and, also in this case, obesity impacted more in the ERα⁺/PR⁺ group.

A molecular circuit of mutual regulation between ERα, PR, HIF1-α, SLUG and miR-221 is feasible in the EC and was firstly suggested by our research. In this interplay miR-221 seems to be in a nodal point of the regulatory system that is particularly strengthened by the metabolic changes in obesity.