Integrated transcriptomic and experimental analysis of FXYD5 associated RAS related programs and tumor microenvironment features in ovarian cancer
Yingying Lv, Hao Cheng, Pengnan ZhangBackground
Ovarian cancer (OC) is characterized by tumor microenvironment remodeling and immune dysregulation.
Methods
We integrated bulk, single-cell, and spatial transcriptomic data with co-expression, immunotherapy-response, pan-cancer, and exploratory machine-learning analyses. FXYD5 was examined in ovarian cancer cells using silencing, overexpression, phenotypic assays, and captopril or losartan treatment.
Results
FXYD5 was upregulated in OC and showed opposite patterns in ovarian cancer- and exercise-responsive datasets. Higher expression was associated with shorter overall survival, ACE-AGTR1-TGFB1-related transcription, and inflammatory, stromal, angiogenic, epithelial-mesenchymal transition (EMT), and immune-checkpoint signatures. In a 32-patient anti-PD-1 cohort, FXYD5 expression differed between responders and non-responders, without independent validation. Single-cell and spatial analyses linked FXYD5 to malignant epithelial and myeloid compartments and macrophage- and fibroblast-enriched regions. FXYD5 silencing reduced cell viability and colony formation, whereas overexpression produced opposite effects and altered the expression of genes related to the renin–angiotensin system (RAS) and EMT. Captopril and losartan reduced viability in FXYD5-overexpressing cells, but missing matched drug controls precluded attribution to FXYD5-specific RAS dependence. Pan-cancer associations were context dependent.
Conclusions
FXYD5 is associated with adverse clinical and microenvironmental features and RAS/TGFB1-related programs in OC, but its mechanistic and therapeutic roles require further validation.