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.