NEAT1-miR-125b-5p-SLC1A5级联的破坏决定了头颈部鳞状细胞癌的致癌性和不同的免疫特征。

IF 6.1 2区 生物学 Q1 CELL BIOLOGY
Ying-Chieh Liu, So-Yu Liu, Yu-Cheng Lin, Chung-Ji Liu, Kuo-Wei Chang, Shu-Chun Lin
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引用次数: 0

摘要

代谢重编程使恶性头颈部鳞状细胞癌(HNSCC)得以克服紧张的微环境,而谷氨酰胺摄取量的增加是癌症中常见的代谢标志。由于代谢重编程已被视为肿瘤细胞的新治疗靶点,因此了解谷氨酰胺摄取在 HNSCC 中的调控轴及其在 HNSCC 发病机制中的潜在下游效应将大有裨益。对癌症基因组图谱(TCGA)-HNSCC 数据集进行的生物信息学分析和对 HNSCC 进行的 RNAseq 分析表明,在 SLC1A 家族的七个同源谷氨酸或中性氨基酸转运体中,SLC1A5 是最失调的转运体。为了进一步明确 SLC1A5 在 HNSCC 中的作用,我们敲除了 SLC1A5 的表达。敲除SLC1A5可减缓细胞生长,诱导G0/G1停滞,降低致瘤性,并增加caspase3、LC3B和细胞内Fe2+的裂解。抑制细胞凋亡、自噬或铁突变的抑制剂可挽救被 SLC1A5 敲除抑制的细胞活力。SLC1A5 敲除还抑制了谷氨酰胺的摄取,增强了氧化应激,并提高了对顺铂的敏感性。CRISPR/dCas9 介导的 SLC1A5 诱导可赋予顺铂抗性,并减少细胞凋亡、自噬和铁变态反应。报告实验和 Western 印迹数据表明,miR-125b-5p 靶向并削弱了 SLC1A5,而 si-NEAT1 则增加了 miR-125b-5p 的表达。对TCGA-HNSCC数据库的分析表明,肿瘤中NEAT1的上调和miR-125b-5p的下调以及SLC1A5的上调是一致的。转录组数据分析显示,SLC1A5表达较高的肿瘤,其CD8+、单核细胞和树突状细胞的免疫评分明显较低,而M0和M1巨噬细胞的评分较高。免疫调节、新陈代谢和氧化应激成分的紊乱与 HNSCC 中 SLC1A5 的畸变有关。本研究得出结论:NEAT1/miR-125b-5p/SLC1A5 级联调节头颈部/口腔癌中致癌性、治疗效果和免疫细胞特征的各种活动。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The disruption of NEAT1-miR-125b-5p-SLC1A5 cascade defines the oncogenicity and differential immune profile in head and neck squamous cell carcinoma.

The disruption of NEAT1-miR-125b-5p-SLC1A5 cascade defines the oncogenicity and differential immune profile in head and neck squamous cell carcinoma.

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.

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来源期刊
Cell Death Discovery
Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
8.30
自引率
1.40%
发文量
468
审稿时长
9 weeks
期刊介绍: Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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