miR-152-3p Overcomes Temozolomide Resistance in Glioblastoma by Targeting TGF-α and Enhancing Apoptosis

Objectives: Temozolomide (TMZ) resistance remains a major challenge in glioblastoma (GBM) treatment. This study investigated the role of miR-152-3p and its downstream target, transforming growth factor-α (TGF-α), in regulating TMZ sensitivity in GBM. Methods: Public GEO and CGGA datasets were analyzed to evaluate the expression and prognostic significance of miR-152-3p. TMZ-resistant GBM cell lines (U87MGR and DBTRG-05MGR) were established by continuous TMZ exposure. Gain- and loss-of-function experiments were performed using miR-152-3p mimics and inhibitors. Cell viability, apoptosis, and TGF-α expression were assessed by MTT, qRT-PCR, and Western blot analyses. Results: miR-152-3p expression was significantly decreased in recurrent GBM and was associated with poor overall survival. TMZ-resistant GBM cells exhibited lower miR-152-3p expression than parental cells. Bioinformatic analyses identified TGF-α as a potential target of miR-152-3p. Overexpression of miR-152-3p suppressed TGF-α expression, reduced cell viability, and enhanced TMZ-induced apoptosis in resistant GBM cells. TGF-α knockdown similarly restored TMZ sensitivity. Conversely, inhibition of miR-152-3p increased TGF-α expression and attenuated TMZ-induced apoptotic signaling in TMZ-sensitive M059K cells. Conclusion: Together, our findings demonstrate that the miR-152-3p/TGF-α axis plays a critical role in regulating TMZ sensitivity in GBM, and targeting this pathway may represent a therapeutically relevant signaling axis to overcome chemoresistance.