Shaikh Khalida, Iqbal Yusra, Abdel-Maksoud Mostafa A, Murad Amina, Badar Nadia, Alarjani Khaloud Mohammed, Siddiqui Komal, Chandio Khushboo, Almanaa Taghreed N, Jamil Muhammad, Ali Mubarik, Jabeen Norina, Hussein Ahmed M
Liaquat University of Medical and Health Sciences Jamshoro, Pakistan.
Continental Medical College Lahore Lahore 54660, Pakistan.
Am J Transl Res. 2023 Jul 15;15(7):4829-4850. eCollection 2023.
Head and neck squamous cell carcinoma (HNSC), a prevalent malignant tumor with a low survival rate, is often accompanied by ferroptosis, which is a recently-described type ofprogrammed cell death. Investigating the significance of ferroptosis driver genes in HNSC, this study aimed to assess their diagnostic and prognostic values, as well as their impact on treatment and tumor immune function. The results of this investigation provide novel insight into using ferroptosis-related genes as molecular biomarkers as well as precise chemotherapeutic targets for the therapy of HNSC.
A detailed in silico and in vitro experiment-based methodology was adopted to achieve the goals.
A total of 233 ferroptosis driver genes were downloaded from the FerrDB database. After comprehensively analyzing these 233 ferroptosis driver genes by various TCGA databases, RNA-sequencing (RNA-seq), and Reverse Transcription Quantitative Real-Time Polymerase Chain Reaction (RT-qPCR) techniques, TP53 (tumor protein 53), PTEN (Phosphatase and TENsin homolog deleted on chromosome 10), KRAS (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), and HRAS (Harvey Rat sarcoma virus) were identified as differentially expressed hub genes. Interestingly, these hub genes were found to have significant (P < 0.05) variations in their mRNA and protein expressions and effects on overall survival of the HNSC patients. Moreover, targeted bisulfite-sequencing (bisulfite-seq) analysis revealed that promoter hypomethylation pattern was associated with up-regulation of hub genes (TP53, PTEN, KRAS, and HRAS). In addition to this, hub genes were involved in diverse oncogenic pathways.
Since HNSC pathogenesis is a complex process, using ferroptosis driver hub genes (TP53, PTEN, KRAS, and HRAS) as a diagnostic and prognostic tool, and therapeutically targeting those genes through appropriate drugs could bring a milestone change in the drug discovery and management and survival in HNSC.
头颈部鳞状细胞癌（HNSC）是一种常见的恶性肿瘤，生存率较低，常伴有铁死亡，这是一种最近描述的程序性细胞死亡类型。本研究旨在探讨铁死亡驱动基因在HNSC中的意义，评估其诊断和预后价值，以及它们对治疗和肿瘤免疫功能的影响。本研究结果为将铁死亡相关基因用作分子生物标志物以及HNSC治疗的精确化疗靶点提供了新的见解。
采用基于计算机模拟和体外实验的详细方法来实现目标。
从FerrDB数据库下载了总共233个铁死亡驱动基因。通过各种TCGA数据库、RNA测序（RNA-seq）和逆转录定量实时聚合酶链反应（RT-qPCR）技术对这233个铁死亡驱动基因进行综合分析后，TP53（肿瘤蛋白53）、PTEN（第10号染色体缺失的磷酸酶和张力蛋白同源物）、KRAS（Ki-ras2 Kirsten大鼠肉瘤病毒癌基因同源物）和HRAS（哈维大鼠肉瘤病毒）被鉴定为差异表达的枢纽基因。有趣的是，这些枢纽基因在其mRNA和蛋白质表达以及对HNSC患者总生存期的影响方面存在显著（P < 0.05）差异。此外，靶向亚硫酸氢盐测序（亚硫酸氢盐测序）分析表明，启动子低甲基化模式与枢纽基因（TP53、PTEN、KRAS和HRAS）的上调有关。除此之外，枢纽基因参与了多种致癌途径。
由于HNSC的发病机制是一个复杂的过程，将铁死亡驱动枢纽基因（TP53、PTEN、KRAS和HRAS）用作诊断和预后工具，并通过适当的药物对这些基因进行治疗靶向，可能会给HNSC的药物发现、管理和生存带来里程碑式的变化。
