Mahjabeen Ishrat, Hussain Muhammad Zahid, Haq Maria Fazal-Ul, Mehmood Azhar, Haris Muhammad Shahbaz, Khan Shereen Ali, Chaudhry Anum, Hakim Farzana, Abbasi Ayesha Zulfiqar, Kayani Mahmood Akhtar
Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan.
Department of Rheumatology, CMH Multan Institute of Medical Sciences, Multan, Pakistan.
Biochem Genet. 2025 Apr 28. doi: 10.1007/s10528-025-11119-x.
Mitochondrial sirtuin 3 (SIRT3) is a gene involved in key functions like acetylation, DNA repair, stress response, and tumorigenesis. Several studies have been published that showed the role of SIRT3 in various cancers. Still, few studies have been reported on the genetic and expression variation of the SIRT3 gene in gastric carcinogenesis. This study was designed to explore the involvement of the SIRT3 gene in gastric cancer. In this study, we used two study cohorts, cohort 1 contained 510 gastric cancer (GC) patients and an equal number of age and gender-matched controls. Cohort 2 included 220 GC tissue samples along with adjacent control tissues. Tetra Arms PCR was used to measure the frequency of three selected SNPs of the SIRT3 gene (rs28365927, rs11246029, and rs3817629) in cohort 1. Quantitative PCR and immunohistochemistry were performed to analyze the SIRT3 expression variation in cohort 2 GC patients. The superoxide dismutase (SOD), and 8-hydroxydeoxyguanosine (8-OHdG) levels were measured using ELISA, and DNA damage was measured using the LORD-Q assay. Statistical analysis showed the significant increased frequency of mutant allele of selected SNPs (rs28365927 (p < 0.0001); rs11246029 (p < 0.0001); and rs3817629 (p < 0.0001) in GC patients compared to controls. Expression analysis results showed significant downregulation of the SIRT3 gene at mRNA level (P < 0.001) and protein level (P < 0.001) in gastric tumor section vs control tissues. Multivariant Cox regression analysis showed that downregulated SIRT3 expression (p < 0.000001), H. pylori status (p < 0.0001), T-stage (p < 0.008), and N-stage (p < 0.001) act as prognostic markers in GC patients. ROC curve analysis showed the 90% and 100% specificity of the SIRT3 gene as a diagnostic marker in GC at the mRNA level and protein level, respectively. Significant increased oxidative stress (antioxidant enzyme level p < 0.0001; 8-OHdG level p < 0.0001) and lesion frequency/10 kb (p < 0.03) were indicated in the gastric tumor tissue sections vs controls. The result showed the tumor suppressor role of the SIRT3 gene in GC and was found linked with the surge in oxidative stress and damage in GC patients.
线粒体去乙酰化酶3（SIRT3）是一种参与乙酰化、DNA修复、应激反应和肿瘤发生等关键功能的基因。已经发表了几项研究，显示了SIRT3在各种癌症中的作用。然而，关于SIRT3基因在胃癌发生中的遗传和表达变异的报道仍然很少。本研究旨在探讨SIRT3基因与胃癌的关系。在本研究中，我们使用了两个研究队列，队列1包含510例胃癌（GC）患者以及数量相等的年龄和性别匹配的对照。队列2包括220份GC组织样本以及相邻的对照组织。采用四臂PCR法检测队列1中SIRT3基因三个选定单核苷酸多态性（SNP）（rs28365927、rs11246029和rs3817629）的频率。采用定量PCR和免疫组织化学方法分析队列2中GC患者的SIRT3表达变异。使用酶联免疫吸附测定法（ELISA）测量超氧化物歧化酶（SOD）和8-羟基脱氧鸟苷（8-OHdG）水平，并使用LORD-Q检测法测量DNA损伤。统计分析表明，与对照组相比，GC患者中选定SNP的突变等位基因频率显著增加（rs28365927（p＜0.0001）；rs11246029（p＜0.0001）；rs3817629（p＜0.0001））。表达分析结果显示，与对照组织相比，胃癌组织切片中SIRT3基因在mRNA水平（P＜0.001）和蛋白质水平（P＜0.001）均显著下调。多变量Cox回归分析表明，SIRT3表达下调（p＜0.000001）、幽门螺杆菌感染状态（p＜0.0001）、T分期（p＜0.008）和N分期（p＜0.001）是GC患者的预后标志物。ROC曲线分析显示，SIRT3基因作为GC诊断标志物在mRNA水平和蛋白质水平的特异性分别为90%和100%。与对照组相比，胃癌组织切片中氧化应激显著增加（抗氧化酶水平p＜0.0001；8-OHdG水平p＜0.0001），且每10 kb的损伤频率（p＜0.03）也显著增加。结果表明SIRT3基因在GC中具有肿瘤抑制作用，并发现其与GC患者氧化应激和损伤的增加有关。
