Context-dependent reconfiguration and spatial reorganisation of the miR-199a-5p/XIAP axis in high-grade serous ovarian cancer

ABSTRACT Background High-grade serous ovarian cancer (HGSOC) is a leading cause of gynaecological cancer mortality, largely because of late diagnosis and platinum resistance. Impaired apoptotic execution is a defining feature of resistant disease, but the regulatory interactions underlying this phenotype remain incompletely understood. The relationship between miR-199a-5p and the anti-apoptotic factor XIAP across cisplatin-sensitive and cisplatin-resistant states was the focus of this study. Methods We investigated the miR-199a-5p/XIAP axis in paired cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer models and in human ovarian tissue using multiplex fluorescence in situ hybridisation and immunofluorescence. Results miR-199a-5p did not show a uniform repressive relationship with XIAP across cellular states. In sensitive cells, miR-199a-5p was consistent with basal XIAP repression and enhanced apoptotic responses following cisplatin exposure. In resistant cells, this relationship was attenuated, suggesting uncoupling between XIAP and apoptotic responsiveness after cisplatin. In human FFPE specimens, spatial analysis identified tumour-associated reorganisation of this axis, with broader miR-199a-5p distribution, greater overlap with XIAP, and a distinct perinuclear pattern in HGSOC. Conclusions The miR-199a-5p/XIAP axis is context-dependent and altered in cisplatin-resistant ovarian cancer. These findings support spatially resolved analysis as a useful framework for identifying regulatory heterogeneity and tumour-associated phenotypes linked to platinum-resistant disease.