Cancer-associated fibroblasts-derived exosomal piR-35462 promotes the progression of oral squamous cell carcinoma via FTO/Twist1 pathway

Abstract Background: Cancer-associated fibroblasts (CAFs) play a critical role in tumor progression. In this study, we explored the influence of exosomal piR-35462 (piR-35462) derived from CAFs on oral squamous cell carcinoma (OSCC) progression. Methods: CAFs and normal fibroblasts (NFs) were obtained from patients-derived samples of OSCC and adjacent normal tissues. Exosomes extracted from CAFs and NFs were confirmed and piRNAs was identified screened. CCK8 assays, EdU and Transwell assays were performed to assess tumor proliferation and metastasis. A nude mouse model was established to assess the impact of exosomal piR-35462 on tumor progression. Results: CAFs-derived exosomes showed a enhanced piR-35462 expression and promoted OSCC cell proliferation, migration and invasion. Additionally, elevated piR-35462 expression in OSCC tissues correlates with poor prognosis. Mechanistically, CAFs-derived exosomal piR-35462 increased the expression of fat mass and obesity-associated protein (FTO) in OSCC cells. By inhibiting N6-methyladenosine (m6A) RNA methylation, the overexpression of FTO further enhances the stability and expression levels of Twist1 mRNA, thereby contributing to epithelial-mesenchymal transition (EMT) and tumor progression. In vivo xenograft tumor model also confirmed the same results. Conclusion: The achieved outcomes elucidate that CAFs can deliver piR-35462 containing exosomes to OSCC cells and promote OSCC progression via FTO/Twist mediated EMT pathways, and could represent a promising therapeutic target for OSCC.