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This review reveals the molecular mechanism by which the Hedgehog (Hh) signaling effector Gli2 promotes carboplatin resistance in epithelial ovarian cancer (EOC) through regulating the core stem cell transcription factor NANOG. Studies indicate that Gli2 overexpression directly drives platinum resistance by upregulating multidrug resistance protein 1 (MDR1) and maintaining the self-renewal and anti-apoptotic capabilities of cancer stem cells (CSCs). Concurrently, NANOG, a core stemness marker, shows expression levels strongly correlated with malignant progression and platinum resistance in EOC. Key evidence reveals a functional link between Gli2 and NANOG: cytoplasmic Gli2 expression positively correlates with NANOG levels, while Gli2 inhibition concurrently downregulates NANOG and MDR1 expression, reversing stemness and chemoresistance. Furthermore, NANOG regulates epithelial-mesenchymal transition (EMT) via the AMPK/mTOR signaling pathway, further reinforcing the CSC phenotype. This review proposes that the Gli2-NANOG axis is a crucial mechanism of acquired carboplatin resistance in EOC, and that targeting this regulatory axis provides a novel strategy to overcome chemoresistance. Future research should focus on elucidating the precise molecular interactions and promoting the clinical translation of related targeted therapies.
Yu et al. (Fri,) studied this question.