代谢重编程维持恶性头颈鳞状细胞癌（HNSCC）克服应激微环境，而谷氨酰胺摄取增加是癌症的常见代谢标志。由于代谢重编程已被认为是肿瘤细胞的新治疗靶点，因此了解 HNSCC 中谷氨酰胺摄取的调节轴及其在 HNSCC 发病机制中的潜在下游影响将非常有益。癌症基因组图谱 (TCGA)-HNSCC 数据集的生物信息分析和对 HNSCC 进行的 RNAseq 分析表明，SLC1A5 是 SLC1A 家族中七个同源谷氨酸或中性氨基酸转运蛋白中失调最严重的转运蛋白。为了进一步阐明 SLC1A5 在 HNSCC 中的作用，我们敲低了 SLC1A5 的表达。这种敲低减慢了细胞生长，诱导 G0/G1 停滞，降低致瘤性，并增加 caspase3、LC3B 和细胞内 Fe2 的裂解。细胞凋亡、自噬或铁死亡的抑制剂可以挽救因 SLC1A5 敲低而受到抑制的细胞活力。 SLC1A5 敲低还抑制谷氨酰胺的摄取，增强氧化应激，并增加对顺铂的敏感性。 CRISPR/dCas9 介导的 SLC1A5 诱导赋予顺铂耐药性并减少细胞凋亡、自噬和铁死亡。报告基因检测和蛋白质印迹数据表明，miR-125b-5p 靶向并减弱 SLC1A5，而 si-NEAT1 则增加 miR-125b-5p 的表达。 TCGA-HNSCC 数据库的分析显示肿瘤中 NEAT1 的上调和 miR-125b-5p 的下调以及 SLC1A5 的上调一致。转录组数据分析显示，SLC1A5 表达较高的肿瘤的 CD8、单核细胞和树突状细胞的免疫评分显着较低，而 M0 和 M1 巨噬细胞的免疫评分较高。免疫调节、代谢和氧化应激成分的破坏与 HNSCC 中的 SLC1A5 畸变相关。本研究得出的结论是，NEAT1/miR-125b-5p/SLC1A5 级联可调节头颈癌/口腔癌的致癌性、治疗效果和免疫细胞特征的多种活性。© 2024。作者。

Metabolic reprogramming sustains malignant head and neck squamous cell carcinoma (HNSCC) to overcome stressful microenvironments, and increased glutamine uptake is a common metabolic hallmark in cancers. Since metabolic reprogramming has been recognized as a new therapeutic target for tumor cells, understanding the regulatory axis of glutamine uptake in HNSCC and its potential downstream effects in its pathogenesis of HNSCC would be incredibly beneficial. Bioinformatic analysis of the Cancer Genome Atlas (TCGA)-HNSCC dataset and RNAseq analysis performed on HNSCC indicated that SLC1A5 was the most dysregulated transporter among the seven homologous glutamate or neutral amino acid transporters in the SLC1A family. To further clarify the role of SLC1A5 in HNSCC, we knocked down SLC1A5 expression. This knockdown decelerated cell growth, induced G0/G1 arrest, diminished tumorigenicity, and increased cleavage caspase3, LC3B, and intracellular Fe2+. Inhibitors against apoptosis, autophagy, or ferroptosis rescued the cell viability repressed by SLC1A5 knockdown. SLC1A5 knockdown also suppressed glutamine uptake, enhanced oxidative stress, and increased sensitivity to cisplatin. CRISPR/dCas9-mediated SLC1A5 induction conferred cisplatin resistance and reduced apoptosis, autophagy, and ferroptosis. Reporter assays and western blot data demonstrated that miR-125b-5p targets and attenuates SLC1A5, while the si-NEAT1 increases miR-125b-5p expression. Analysis of the TCGA-HNSCC databases showed concordant upregulation of NEAT1 and downregulation of miR-125b-5p, along with SLC1A5 upregulation in tumors. Analysis of transcriptomic data revealed that tumors harboring higher SLC1A5 expression had significantly lower immune scores in CD8+, monocytes, and dendritic cells, and higher scores in M0 and M1 macrophages. Disruptions in immune modulation, metabolism, and oxidative stress components were associated with SLC1A5 aberrations in HNSCC. This study concludes that the NEAT1/miR-125b-5p/SLC1A5 cascade modulates diverse activities in oncogenicity, treatment efficacy, and immune cell profiles in head and neck/oral carcinoma.© 2024. The Author(s).