HPV HNSCC-derived exosomal miR-9-5p inhibits TGF-β signaling-mediated fibroblast phenotypic transformation through NOX4.

Human papillomavirus (HPV) is a significant risk factor for head and neck squamous cell carcinoma (HNSCC). HPV HNSCC patients have a higher survival rate, which may be related to its unique tumor microenvironment. Exosomes are emerging as a communication tool between tumor cells and the tumor microenvironment, including cancer-associated fibroblasts (CAFs). In this study, 111 clinical samples tissues and public sequencing data were analyzed. Our study found fewer CAFs infiltrated in HPV HNSCC, and poor CAF infiltration level was associated with a good prognosis. HPV HNSCC cell-derived exosomes can significantly reduce the phenotypic transformation of fibroblasts. miR-9-5p, as a miRNA enriched in HPV HNSCC cell-derived exosomes, can be transferred to fibroblasts. miR-9-5p mimic transfection decreased the expression of NOX4 and the level of intracellular reactive oxygen species (ROS), which inhibited the transforming growth factor beta 1(TGF-β1)-induced increase of αSMA levels. Therefore, these results indicated that HPV HNSCC-derived exosomal miR-9-5p inhibits TGF-β signaling-mediated fibroblast phenotypic transformation through NOX4, which is related to the excellent prognosis of HPV patients.