FXYD5/Dysadherin, a Biomarker of Endometrial Cancer Myometrial Invasion and Aggressiveness: Its Relationship With TGF-β1 and NF-κB Pathways

María José Besso; Marina Rosso; Lara Lapyckyj; Cristian Pablo Moiola; María Laura Matos; María Florencia Mercogliano; Roxana Schillaci; Jaume Reventos; Eva Colas; Antonio Gil-Moreno; Alejandra Wernicke; Roberto Orti; Mónica Hebe Vazquez-Levin

doi:10.3389/fonc.2019.01306

FXYD5/Dysadherin, a Biomarker of Endometrial Cancer Myometrial Invasion and Aggressiveness: Its Relationship With TGF-β1 and NF-κB Pathways

Front Oncol. 2019 Dec 6:9:1306. doi: 10.3389/fonc.2019.01306. eCollection 2019.

Authors

Affiliations

¹ Laboratorio de Estudios de la Interacción Celular en Reproducción y Cáncer, Instituto de Biología y Medicina Experimental (IBYME; CONICET-FIBYME), Buenos Aires, Argentina.
² Biomedical Research Group in Gynecology, Vall d'Hebron Research Institute (VHIR), Universitat Autónoma de Barcelona, CIBERONC, Barcelona, Spain.
³ Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME; CONICET-FIBYME), Buenos Aires, Argentina.
⁴ Gynecological Oncology Department, Vall Hebron University Hospital, CIBERONC, Barcelona, Spain.
⁵ Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.

Abstract

Objective: Endometrial cancer (EC) is the second most common gynecological cancer worldwide. Myometrial invasion (MI) is a key event in EC dissemination. This study aimed to evaluate FXYD5/dysadherin (FXYD5/Dys) expression in EC tissue and uterine aspirate (UA) biopsies and to assess molecular/functional changes associated with its expression in cellular models. Methods: FXYD5/Dys messenger RNA (mRNA) levels were determined in EC tissue and UA biopsies. FXYD5/Dys expression was evaluated in EC RNAseq data from The Cancer Genome Atlas (TCGA) and GENEVESTIGATOR tools. FXYD5/Dys impact on E-cadherin expression and cell behavior was assessed in EC Hec1a cells treated with transforming growth factor (TGF)-β1, stably transfected with ETV5, and transiently transfected with FXYD5/Dys small interfering RNA (siRNA) or pcDNA3-FXYD5/Dys plasmid. Results: FXYD5/Dys was associated with EC aggressiveness, finding high mRNA levels in tumors depicting MI > 50%, Grade 3, and intermediate/high risk of recurrence. FXYD5/Dys was highly expressed at the tumor invasive front compared to the superficial area. Most results were recapitulated in UA biopsies. FXYD5/Dys modulation in Hec1a cells altered cell migration/adhesion and E-cadherin expression. TGF-β1 treatment of Hec1a cells induced FXYD5/Dys expression. TCGA-UCEC RNAseq analysis revealed a positive correlation between FXYD5/Dys, TGF-β1, and plasminogen activator inhibitor (PAI)-1 mRNA levels. FXYD5/Dys induced nuclear factor (NF)-κB pathway activation in Hec1a cells. FXYD5/Dys mRNA levels positively correlated with transcriptional activation of NF-κB p65-regulated genes. Survival analysis revealed patient segregation into low- and high-risk groups, the latter depicting the highest FXYD5/Dys, PAI-1, tumor necrosis factor (TNF)-α, and TGF-β1 mRNA levels and shorter survival rates. Conclusion: FXYD5/Dys is a novel biomarker of EC progression related to TGF-β1 and NF-κB pathways that collectively promote tumor dissemination and result in poor patient prognosis.

Keywords: CCL-2; E-cadherin; FXYD5; NF-κB; TGF-β1; dysadherin; endometrial cancer.