MicroRNA-135 alleviates cisplatin resistance in cervical cancer by inhibiting CD44v6

Abstract: Background: Cervical cancer (CC) remains a leading cause of cancer-related mortality worldwide and cisplatin resistance poses a major challenge to effective treatment. MicroRNA-135 (miR-135) has been implicated in tumor progression and drug resistance, but its role in cisplatin-resistant CC remains unclear. Objectives: To investigate whether miR-135 affects cisplatin resistance in CC cells by targeting CD44v6. Methods: Bioinformatic analysis (TargetScan) was performed to predict the miR-135 binding site in CD44v6, followed by a dual-luciferase reporter assay. RT-qPCR and Western blot were used to measure miR-135 and CD44v6 expression in cisplatin-resistant HeLa/DDP cells, HeLa cells and normal Ect1/E6E7 cells. HeLa/DDP cells were transfected with miR-135 mimic or NC mimic and cell proliferation (CCK-8, colony formation), apoptosis (flow cytometry) and CD44v6 expression were assessed. Results: miR-135 directly bound to the CD44v6 3‘-UTR, reducing luciferase activity by 58% (*p* < 0.001). miR-135 expression was decreased by 68% in HeLa/DDP cells compared to Ect1/E6E7 cells, while CD44v6 expression was increased 3.5-fold. miR-135 mimic transfection reduced CD44v6 protein expression by 62%, decreased cell viability by 57.3%, increased the apoptosis rate from 12.4% to 35.8% (absolute increase of 23.4%) and lowered the cisplatin IC50 from 22.36 to 8.47 μmol/L (2.64-fold reversal, *p* < 0.001). Conclusions: miR-135 overexpression was associated with reduced CD44v6 expression, decreased proliferation, increased apoptosis and enhanced sensitivity to cisplatin in HeLa/DDP cells. These findings demonstrate an inverse association between miR-135 and CD44v6 in cisplatin-resistant CC cells; however, causal mechanistic evidence (e.g., via CD44v6-specific knockdown or rescue experiments) is not provided. Further studies are required to establish whether CD44v6 directly mediates the chemosensitizing effects of miR-135.