Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumours 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 Centre for Stomatology, National Clinical Research Centre for Oral Diseases, Shanghai Research Institute of Stomatology, Shanghai Centre 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 tumour metabolism in OSCC.

Building on previous findings that ADAMTS9-AS2 functions as a tumour suppressor by regulating PI3K-AKT signalling, 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 tumour 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 personalised targeted therapy for the treatment of OSCC.

Source: Compuscript Ltd