Abstract 3800: The disruption of miR-125b-SLC1A5 cascade defines the oncogenicity and differential immune profile in oral carcinoma

Abstract Head and neck squamous carcinoma (HNSCC) including oral SCC (OSCC) is a worldwide malignancy that requires vigorous efforts for interception. The metabolic reprogramming sustains malignant tumor cells to overcome stressful microenvironments. As the glutamine is the one of the essential components which helps cells to erase reactive oxygen species and energy production, the increased uptake of glutamine is a common metabolic hallmark in cancers. Bioinformatic analysis of TCGA HNSCC datasets and RNAseq results in our cohort indicated that solute carrier family 1 member 5 (SLC1A5) is the most eminently dysregulated transporter member among the seven glutamate or neutral amino acid transporters in SLC1A family. This work identified that the knockdown of SLC1A5 expression decreased in vitro oncogenicity, xenografic tumorigenesis and glutamine uptake; increased oxidative stress, cell cycle arrest, and sensitivity to cisplatin and ferroptosis inducer in OSCC cells. By way of contrast, the upregulation of endogenous SLC1A5 expression mediated by CRISPR/dCas9 activation system drove the OSCC oncogenesis. The reporter assay and functional analysis demonstrated that suppressor miRNA miR-125b targeted and attenuated SLC1A5, while NEAT1 lncRNA sponged and ablated miR-125b-SLC1A5 axis. The analysis of TCGA and GEO datasets confirmed the concordant upregulation of NEAT1 and downregulation of miR-125b along with the SLC1A5 upregulation in tumors. Besides, SLC1A5 upregulation defined the worse HNSCC patient survival. In our tumor cohort, OSCC harboring higher SLC1A5 expression had lower CD4+ immune score, and higher scores in M0 and M1 macrophage. GSEA algorithm further deciphered that tumors having higher SLC1A5 expression manifested the repression in glycolysis, apoptosis and p53 signaling. This study concludes that the frequent disruption of NEAT1-miR-125b-SLC1A5 cascade modulates the pluripotent oncogenic activities, the treatment efficacy and the immune landscape in oral carcinoma. Citation Format: Ying-Chieh Liu, So-Yu Liu, Yu-Cheng Lin, Chung-Ji Liu, Kuo-Wei Chang, Shu-Chun Lin. The disruption of miR-125b-SLC1A5 cascade defines the oncogenicity and differential immune profile in oral carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3800.