Mechanism of miR-188-5p enhancing radioresistance in nasopharyngeal carcinoma by targeting PTEN to activate the PI3K/Akt signaling pathway

Background: Radiotherapy resistance remains a critical obstacle in nasopharyngeal carcinoma (NPC) treatment, yet the underlying mechanisms are not fully understood. Although miR-188-5p has been implicated in the malignant progression of various tumors, its role in NPC radioresistance requires further investigation. This study aims to explore whether miR-188-5p mediates radioresistance by targeting PTEN to activate the PI3K/AKT signaling pathway and induce epithelial-mesenchymal transition (EMT).

Methods: Radioresistant NPC cell lines C666-1R were established. Cell proliferation and radioresistance were evaluated using Cell Counting Kit-8 (CCK-8) and colony forming assays. C666-1R cells were transfected with miR-188-5p inhibitor/mimic and sh-PTEN, followed by 4 Gy irradiation. Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, Transwell assay, wound healing assay, flow cytometry, and dual-luciferase reporter assay were performed to assess the effects of miR-188-5p on cell proliferation, invasion, migration, apoptosis, and the PTEN/PI3K/AKT pathway.

Results: Radioresistant NPC cell lines were successfully established and validated. miR-188-5p was highly expressed in NPC tissues and NPC cell lines, particularly in the radioresistant C666-1R cells. Inhibition of miR-188-5p enhanced radiosensitivity, as evidenced by reduced cell viability, invasion, migration, and increased apoptosis. Dual-luciferase reporter assay confirmed that miR-188-5p directly bound to the 3'-UTR of PTEN and suppressed its expression. Rescue experiments demonstrated that PTEN knockdown reversed the miR-188-5p inhibition-induced suppression of PI3K/AKT activity and EMT phenotype, restoring p-PI3K, p-AKT, N-cadherin, and Vimentin levels while downregulating E-cadherin. These findings indicate that miR-188-5p activates the PI3K/AKT pathway and promotes EMT by directly targeting PTEN, thereby mediating NPC radioresistance.

Conclusions: miR-188-5p enhances radioresistance in NPC cells by suppressing PTEN expression, relieving its negative regulation of the PI3K/AKT signaling pathway, activating this pathway, and inducing EMT. Thus, inhibiting miR-188-5p may represent a promising strategy to overcome radioresistance in NPC.