Regulation of doxorubicin resistance and cellular metabolism by miR-203a-3p via p53 and TAp63 signaling in hepatocellular carcinoma
Résumé
Doxorubicin (DOX) is a cornerstone chemotherapeutic drug in the treatment of hepatocellular carcinoma (HCC). However, its efficacy is often limited by the development of drug resistance linked to increased cellular capacity to repair DNA damage. Altered tumor metabolism allows cancer cells to meet increased energy demands for rapid proliferation while evading apoptosis and adapting to therapeutic interventions. MiR-203a-3p is associated with regulating members of the p53 family and has been implicated in regulating chemoresistance and metabolic rewiring in various cancers, yet its role in HCC remains to be elucidated. This study investigated the functional role of miR-203a-3p in response to DOX in HCC cell lines differing in p53 status. HepG2 (wild-type p53) and Huh7 (mutant p53) cells were transfected with miR-203a-3p mimics or inhibitors, alone or in combination with DOX. Cell viability was assessed by MTT assay, and the expression levels of p53 family members and Bax were measured by qPCR. Apoptosis was evaluated by flow cytometry, and mitochondrial function was examined using the Seahorse XFe96 analyzer. MiR-203a-3p expression was significantly higher in DOX-resistant HepG2 cells relative to DOX-sensitive Huh7 cells. In HepG2 cells, miR-203a-3p promoted resistance through p53/Δ133p53-driven survival and enhanced oxidative phosphorylation. In Huh7 cells, it suppressed TAp63/Bax-mediated apoptosis while driving both oxidative phosphorylation and glycolysis, promoting resistance despite the absence of wild-type p53. These findings identify miR-203a-3p as a key modulator of DOX resistance in HCC through coordinated regulation of p53 family expression, apoptotic signaling, and metabolic rewiring, highlighting its potential as a therapeutic target for miRNA-based combination therapies.
Citer ce document
Accès au document
Texte intégral en lecture en ligne, réservé aux abonnés SPHAERO et aux membres de l'institution. Se connecter
Voir l'article sur le site de la revueAuteur(s)
Statistiques
Consultations : 1
Téléchargements : 0