image: (A, B) Expression levels (A) and fold changes (B) of the top 10 differential miRNA expression by exosomal ADAMTS9-AS2 in CAL27 cells. (C) Relative let-7a-5p expression in samples of patients at different stages of the disease. (D) Quantitative reverse transcription PCR was used to analyze ADAMTS9-AS2 and let-7a-5p levels after ADAMTS9-AS2 knockdown in HOK cells. (E) Glucose uptake, lactate production, ATP levels, and O2 consumption were measured in CAL27 cells transfected with non-targeting control (NTC) or let-7a-5p mimics. (F) Quantitative reverse transcription PCR analysis of let-7a expression in CAL27 cells transfected with NTC or let-7a-5p antagomirs. Glucose uptake, lactate production, and ATP levels were measured in CAL27 cells transfected with NTC or let-7a-5p antagomirs. The data were presented as mean ± standard deviation of three independent experiments by student's t-test. *P < 0.05, **P < 0.01, ***P < 0.001. A9-AS2, ADAMTS9-AS2; Exos, exosomes.
Credit: Shanghui Zhou, Jingyu Zhan, Jia Wang, Jingang Yang, Dahe Zhang, Zhenming Li, Yue He
Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of the head and neck. Oral submucous fibrosis (OSF), which develops into OSCC, has become a relatively common pathway in oral mucosal carcinogenesis, with a transformation rate ranging from 3% to 19%. Hence, it is critical to elucidate the key molecular events of OSF tumorigenesis for the prevention and early diagnosis of OSCC.
In a recent study published in Genes & Diseases, researchers from several institutions, including Shanghai Jiao Tong University School of Medicine, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Research Institute of Stomatology, Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Hainan West Central Hospital, and Shanghai Jiao Tong University explored the role of the long non-coding RNA ADAMTS9-AS2 in modulating tumor metabolism in OSCC. Building on previous findings that ADAMTS9-AS2 functions as a tumor suppressor by regulating PI3K-AKT signaling, this study focuses on its involvement in cancer metabolic reprogramming.
Researchers conducted a transcriptomic analysis of OSCC-OSF progression using samples from normal oral mucosa, OSF, and OSCC-OSF tissues and identified significant enrichment of metabolic pathways during the transition from OSF to OSCC. Notably, exosomes enriched with ADAMTS9-AS2 reduced glucose uptake and lactate production while increasing oxygen consumption in OSCC cells, confirming its inhibitory role in aerobic glycolysis, also known as the Warburg effect.
Furthermore, an up-regulation of let-7a-5p, a tumor suppressive miRNA, was observed in ADAMTS9-AS2-Exos-treated cells. Using siRNA-mediated knockdown of ADAMTS9-AS2, it was further confirmed that ADAMTS9-AS2 expression is required for let-7a-5p up-regulation, suggesting positive regulation between ADAMTS9-AS2 and let-7a-5p in OSCC tissues. Interestingly, let-7a-5p directly suppresses the glycolytic enzyme HK2 (hexokinase 2) by binding to its 3′-UTR, thereby downregulating glycolysis. Knockdown of HK2 reversed the glycolytic changes induced by let-7a-5p inhibition, signifying the importance of the ADAMTS9-AS2/let-7a-5p/HK2 axis as a promising therapeutic target for OSCC patients.
Ultra-high-performance liquid chromatography and mass spectrometry revealed that exosomal ADAMTS9-AS2 regulated metabolic reprogramming in OSCC cells. A total of 926 metabolites were identified, with significant alterations in lipid metabolism, pyrimidine metabolism, and the citrate (TCA) cycle. Notably, levels of DL-glutamic acid and D-mannose were increased, while cytidine and D-maltose were decreased following exosome treatment.
In summary, this study highlights the importance of the ADAMTS9-AS2/let-7a-5p/HK2 axis in controlling the Warburg effect and OSCC progression. It also provides a global profile of metabolic reprogramming with ADAMTS9-AS2 exosome treatment, which may lead to the development of personalized targeted therapy for the treatment of OSCC.
Reference
Title of Original Paper: lncRNA ADAMTS9-AS2/let-7a-5p axis regulates metabolic reprogramming by targeting HK2 in oral submucous fibrosis-associated oral squamous cell carcinoma
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101670
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