Exosome‐derived long non‐coding RNA ADAMTS9‐AS2 suppresses progression of oral submucous fibrosis via AKT signalling pathway

Oral submucosal fibrosis (OSF) is one of the pre‐cancerous lesions of oral squamous cell carcinoma (OSCC). Its malignant rate is increasing, but the mechanism of malignancy is not clear. We previously have elucidated the long non‐coding RNA (lncRNA) expression profile during OSF progression at the genome‐wide level. However, the role of lncRNA ADAMTS9‐AS2 in OSF progression via extracellular communication remains unclear. lncRNA ADAMTS9‐AS2 is down‐regulated in OSCC tissues compared with OSF and normal mucous tissues. Low ADAMTS9‐AS2 expression is associated with poor overall survival. ADAMTS9‐AS2 is frequently methylated in OSCC tissues, but not in normal oral mucous and OSF tissues, suggesting tumour‐specific methylation. Functional studies reveal that exosomal ADAMTS9‐AS2 suppresses OSCC cell growth, migration and invasion in vitro. Mechanistically, exosomal ADAMTS9‐AS2 inhibits AKT signalling pathway and regulates epithelial‐mesenchymal transition markers. Through profiling miRNA expression profile regulated by exosomal ADAMTS9‐AS2, significantly enriched pathways include metabolic pathway, PI3K‐Akt signalling pathway and pathways in cancer, indicating that exosomal ADAMTS9‐AS2 exerts its functions through interacting with miRNAs during OSF progression. Thus, our findings highlight the crucial role of ADAMTS9‐AS2 in the cell microenvironment during OSF carcinogenesis, which is expected to become a marker for early diagnosis of OSCC.