Oral squamous cell carcinoma in the background of/with oral submucous fibrosis(OSCC-OSF)has a unique etiology and is clinically distinct from other OSCCs.We previously identified ADAMTS9-AS2 as a functional tumor supp...Oral squamous cell carcinoma in the background of/with oral submucous fibrosis(OSCC-OSF)has a unique etiology and is clinically distinct from other OSCCs.We previously identified ADAMTS9-AS2 as a functional tumor suppressor in OSCC-OSF through the regulation of PI3K-AKT signaling.However,its role in metabolic modulation and the underlying mechanisms remain unclear.In this study,we reported for the first time that ADAMTS9-AS2 suppressed aerobic glycolysis by cooperating with let-7a-5p in OSCC cells.Mechanistically,let-7a-5p inhibited HK2 expression by targeting its 3′-UTR,further deregulating glycolytic function,while enhancing HK2 expression rescued the inhibitory effects of the ADAMTS9-AS2/let-7a-5p axis on aerobic glycolysis and OSCC cell growth.Exosomal ADAMTS9-AS2 regulated metabolic reprogramming during OSCC tumorigenesis.ABC transporters in lipid and pyrimidine metabolism were significantly enriched pathways.Changes in several key metabolites were identified after ADAMTS9-AS2 exosome treatment,including increased levels of DL-glutamic acid and D-mannose,along with decreased levels of cytidine and D-maltose.Thus,our findings demonstrate that ADAMTS9-AS2 drives let-7a-5p binding to HK2 to suppress cell growth in OSCC by abolishing aerobic glycolysis.Our data on metabolic reprogramming have greatly expanded the role of the ADAMTS9-AS2/let-7a-5p axis as a key regulator of metabolism during OSCC tumorigenesis.展开更多
基金supported by the National Natural Science Foundation of China(No.82460458)the Natural Science Foundation of Shanghai,China(No.21ZR1438200).
文摘Oral squamous cell carcinoma in the background of/with oral submucous fibrosis(OSCC-OSF)has a unique etiology and is clinically distinct from other OSCCs.We previously identified ADAMTS9-AS2 as a functional tumor suppressor in OSCC-OSF through the regulation of PI3K-AKT signaling.However,its role in metabolic modulation and the underlying mechanisms remain unclear.In this study,we reported for the first time that ADAMTS9-AS2 suppressed aerobic glycolysis by cooperating with let-7a-5p in OSCC cells.Mechanistically,let-7a-5p inhibited HK2 expression by targeting its 3′-UTR,further deregulating glycolytic function,while enhancing HK2 expression rescued the inhibitory effects of the ADAMTS9-AS2/let-7a-5p axis on aerobic glycolysis and OSCC cell growth.Exosomal ADAMTS9-AS2 regulated metabolic reprogramming during OSCC tumorigenesis.ABC transporters in lipid and pyrimidine metabolism were significantly enriched pathways.Changes in several key metabolites were identified after ADAMTS9-AS2 exosome treatment,including increased levels of DL-glutamic acid and D-mannose,along with decreased levels of cytidine and D-maltose.Thus,our findings demonstrate that ADAMTS9-AS2 drives let-7a-5p binding to HK2 to suppress cell growth in OSCC by abolishing aerobic glycolysis.Our data on metabolic reprogramming have greatly expanded the role of the ADAMTS9-AS2/let-7a-5p axis as a key regulator of metabolism during OSCC tumorigenesis.
