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 regulator 5 (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 in vitro (Transwell assay, clonogenic assay and western blot analysis) and in vivo (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 E3 ubiquitin protein ligase 2-TGF-β receptor 1 (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.

MMP8 increases tongue carcinoma cell–cell adhesion and diminishes migration via cleavage of anti-adhesive FXYD5

“…Hence, our results in OTSCC cells strengthens the previous findings for the tumour-promoting role of FXYD5 in other cancers. Breast cancer cells overexpressing FXYD5 metastasize more compared to controls 36 and similar findings were shown in ovarian cancer 58 . FXYD5 also disperses the TβR1 complex leading to enhanced TGF-β signalling and SMAD3/4 activation, which in turn upregulates FXYD5 gene expression in ovarian cancer 58 .…”

Stromal POSTN induced by TGF-β1 facilitates the migration and invasion of ovarian cancer

“…Informed consent was obtained from all patients prior to the study. Immunohistochemical staining was conducted as described previously [20]. Immunostaining scores of POSTN in stromal and tumor components were assessed using a scoring system encompassing staining intensity (0 = none, 1 = weak, 2 = moderate, 3 = strong) and positivity percentage (0 ≤5%, 1 = 5-25%, 2 = 26-50%, 3 = 51-75%, 4 = 76-100%); the product of the scores produced a final score ranging from 0 to 12.…”

Role of exosomes in the immune microenvironment of ovarian cancer (Review)

“…The high expression of TGF-β3 is associated with poor prognosis of high-grade serous carcinoma, and it is a potential indicator for the evaluation of ovarian cancer prognosis (57). Recent studies have reported that in ovarian cancer stem cells, inhibition of TGF-β/SMAD pathway activation can further inhibit EMT (58)(59)(60). In 2012, Kulbe et al (61) first described the 'TNF' network in the ovarian cancer microenvironment.…”