Huanjie Zhao, Bukhari Ihtisham, Fazhan Li, Wen Huijuan, Wang Jingyun, Wanqing Wu, Yuming Fu, Youcai Tang, AlJowaie Reem M, Aziz Ibrahim M, Xiufeng Chu, Yang Mi, Pengyuan Zheng
Henan Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, ErQi 450052, Zhengzhou, Henan, China.
Department of Gastroenterology, Fifth Affiliated Hospital of Zhengzhou University, ErQi, 450052, Zhengzhou, Henan, China.
Heliyon. 2024 Jul 26;10(15):e35228. doi: 10.1016/j.heliyon.2024.e35228. eCollection 2024 Aug 15.
TP53, a guardian of the genome, suppresses or enhances tumors through various regulatory pathways. However, the role of p53-related long non-coding RNAs (lncRNAs) in immune regulation of tumor microenvironment and prognosis of gastric cancer (GC) is so far unelucidated. We analyzed the role of TP53-associated lncRNAs (obtained from the TP53LNC-DB database) in immune regulation, immune cell infiltration and RNA modification in gastric cancer. Firstly, using multivariate COX regression analysis, we identified eight lncRNAs related to the prognosis of GC. Furthermore, based on the expression of the lncRNA signature and risk score, the GC patients were divided into high-risk and low-risk groups. We found that M2-macrophages have significantly higher infiltration in the high-risk group. Similarly, significant differences in immune function (APC_co_stimulation, CCR, and checkpoint) and mA modification (FTO, ZC3H13, YTHDC1, and RBM15), and mC modification (NOP2 and TET1) between both groups were also observed. These signature lncRNAs were also positively associated with oxidative stress-related genes (MPO, MAPK14, HMOX1, and APP). Additionally, we found that high expression of GAS5 and low expression of MALAT1 in Helicobacter pylori (H-pylori) positive GC patients. Finally, GC patients in the low-risk group showed higher resistance to immunotherapy while patients in the high-risk group were more sensitive to various chemotherapy drugs. Based on these findings, we conclude that p53-associated lncRNAs signature could potentially predict the immune status and overall survival, and may also be used for risk management and planning immunotherapy for gastric cancer patients.
TP53作为基因组的守护者，通过多种调控途径抑制或促进肿瘤。然而，p53相关长链非编码RNA（lncRNA）在肿瘤微环境免疫调节及胃癌（GC）预后中的作用迄今仍未阐明。我们分析了TP53相关lncRNA（从TP53LNC-DB数据库获得）在胃癌免疫调节、免疫细胞浸润和RNA修饰中的作用。首先，通过多变量COX回归分析，我们鉴定出8种与GC预后相关的lncRNA。此外，根据lncRNA特征和风险评分的表达，将GC患者分为高风险组和低风险组。我们发现高风险组中M2巨噬细胞的浸润显著更高。同样，两组之间在免疫功能（抗原呈递细胞协同刺激、趋化因子受体和检查点）和N6-甲基腺嘌呤（mA）修饰（脂肪量和肥胖相关蛋白、锌指CCCH型包含13、YTH结构域含RNA结合蛋白1和RNA结合基序蛋白15）以及5-甲基胞嘧啶（mC）修饰（NOP2和TET1）方面也观察到显著差异。这些特征性lncRNA还与氧化应激相关基因（髓过氧化物酶、丝裂原活化蛋白激酶14、血红素加氧酶1和淀粉样前体蛋白）呈正相关。此外，我们发现幽门螺杆菌（H-pylori）阳性GC患者中生长停滞特异性转录本5（GAS5）高表达而转移相关肺腺癌转录本1（MALAT1）低表达。最后，低风险组的GC患者对免疫治疗表现出更高的抗性，而高风险组的患者对各种化疗药物更敏感。基于这些发现，我们得出结论，p53相关lncRNA特征可能潜在地预测免疫状态和总生存期，也可用于胃癌患者的风险管理和免疫治疗规划。
