Abstract 2802: Circular RNA variants of the<i>NUMB</i> gene modulate the oncogenicity of oral squamous cell carcinoma

Abstract NUMB adaptor protein confers pleiotropic biological and pathological functions by binding with ubiquitin ligases to break down targeted molecules and other activities. Our previous studies have identified that NUMB protein suppresses oral squamous cell carcinoma (OSCC) oncogenicity, and it binds monocarboxylate transporters to elicit the degradation and the associated metabolic disruption. Besides, several oncogenic miRNAs co-target NUMB to abrogate its activity. However, in the TCGA head and neck squamous cell carcinoma (HNSCC) dataset and our OSCC cohort, NUMB expression is slightly unregulated. Despite several isoforms of NUMB owing to alternative slicing, our studies have disclosed the resemblance in oncogenic potential from different NUMB isoforms. Circular RNAs deriving from exons' back-splicing are new RNA entities mediating versatile biological functions. This study identifies several uncharacterized circular RNA variants of the NUMB gene (circNUMBs) in OSCC cell lines and tissues. Following the induction of NUMB promoter activity using the Crispr SAM activation system, the endogenous linear and circular NUMBs are upregulated similarly. The NUMB-null cell subclones, devoid of linear and circular NUMB transcripts, exhibit decreased oncogenicity. However, circNUMBs expression increases the oncogenicity of parental OSCC cells, and it profoundly reverses oncogenic phenotypes of cell subclones as being repressed by NUMB deletion. Analysis using transcriptomic algorithms reveals that circNUMBs modulate cancer, cell development, cell injury, and cell movement genes. The MYC and WNT/β-catenin are the leading signals affected by circNUMBs. This study concludes that circNUMBs mediate oncogenic functions opposite to linear NUMB transcript. Illuminating the interplay of linear NUMB, circNUMB, and their effectors would enable mechanistic insight into HNSCC/OSCC pathogenesis associated with NUMB expression. Citation Format: Chung-Hsien Chou, Pin-Yu Chen, Shu-Chun Lin, Kuo-Wei Chang. Circular RNA variants of theNUMB gene modulate the oncogenicity of oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2802.