A FXYD5/TGF‑β/SMAD positive feedback loop drives epithelial‑to‑mesenchymal transition and promotes tumor growth and metastasis in ovarian cancer.

Abstract

Epithelial ovarian cancer is aggressive and lacks effective prognostic indicators or therapeutic targets. In the present study, using immunohistochemistry and bioinformatics analysis on ovarian cancer tissue data from The Obstetrics and Gynecology Hospital of Fudan University and The Cancer Genome Atlas database, it was identified that FXYD domain‑containing ion transport regulator5 (FXYD5) expression was upregulated in the SKOV3‑IP cell line compared with its parental cell line, SKOV3, and in ovarian cancer tissues compared with in normal tissues. In addition, FXYD5 upregulation was predictive of poor patient survival. Furthermore, through various invitro (Transwell assay, clonogenic assay and western blot analysis) and invivo (nude mouse model) experiments, it was demonstrated that FXYD5 promoted the metastasis of ovarian cancer cells. Mechanistically, RNA sequencing, western blot analysis, a luciferase reporter assay and chromatin immunoprecipitation were performed to reveal that FXYD5 dispersed the SMAD7‑SMAD specific E3ubiquitin protein ligase2‑TGF‑β receptor1 (TβR1) complex, deubiquitinated and stabilized TβR1, and subsequently enhanced transforming growth factor‑β (TGF‑β) signaling and sustained TGF‑β‑driven epithelial‑mesenchymal transition (EMT). The TGF‑β‑activated SMAD3/SMAD4 complex was in turn directly recruited to the FXYD5 promoter region, interacted with specific SMAD‑binding elements, and then promoted FXYD5 transcription. In brief, FXYD5 positively regulated TGF‑β/SMADs signaling activities, which in turn induced FXYD5 expression, creating a positive feedback loop to drive EMT in the process of ovarian cancer progression. Collectively, the findings of the present study suggested a mechanism through which FXYD5 serves a critical role in the constitutive activation of the TGF‑β/SMADs signaling pathways in ovarian cancer, and provided a promising therapeutic target for human ovarian cancer.