Li Na, Zhan Xianquan
Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, 440 Jiyan Road, Jinan, Shandong 250117, China.
Medical Science and Technology Innovation Center, Shandong First Medical University, Jinan, 6699 Qingdao Road, Jinan, Shandong 250117, China.
Oxid Med Cell Longev. 2022 Feb 17;2022:8450087. doi: 10.1155/2022/8450087. eCollection 2022.
Oxidative stress produced a large amount of reactive oxygen species (ROS), which played a pivotal role in balanced ability and determining cell fate. The activated Nrf2 signaling pathway that responds to the excessive ROS regulated the expressions of antiapoptotic proteins, antioxidative enzymes, drug transporters, and detoxifying factors.
The Nrf2 signaling pathway-related genes that had a direct relationship with Nrf2, including ATF4, BACH1, CREBBP, CUL3, EIF2AK3, EP300, FOS, FOSL1, GSK3B, JUN, KEAP1, MAF, MAFF, MAFG, MAFK, MAPK1, MAPK3, MAPK7, MAPK8, MAPK9, PIK3CA, PRRT2, and RIT1, were selected to do a systematic pan-cancer analysis. The relationship of Nrf2 signaling pathway-related gene expressions with tumor mutation burden, microsatellite status, clinical characteristics, immune system, cancer stemness index, and drug sensitivity was calculated by the Spearson correlation analysis across 11,057 subjects representing 33 cancer types. The prognosis models in lung squamous carcinoma, breast cancer, and stomach cancer were constructed with the Cox multivariate regression analysis and least absolute shrinkage and selection operator (Lasso) regression.
Many Nrf2 signaling pathway-related genes were differently expressed between tumor and normal tissues. PIK3CA showed high mutation rate in pan-cancer. The expressions of Nrf2 signaling pathway-related genes were significantly related to tumor mutation burden, copy number variant, microsatellite instability score, survival rate, pathological stage, immune phenotype, immune score, immune cell, cancer stemness index, and drug sensitivity. The prognosis models were significantly associated with survival rate in lung squamous carcinoma, breast cancer, and stomach cancer; and the prognosis model-based riskscore was significantly associated with clinicopathological characteristics of each cancer.
The study provided a comprehensive pan-cancer landscape of Nrf2 pathway-related genes. Based on the same Nrf2 pathway-related genes, the different prognosis models were constructed for different types of cancers.
氧化应激产生大量活性氧（ROS），其在平衡能力和决定细胞命运中起关键作用。对过量ROS作出反应而激活的Nrf2信号通路调节抗凋亡蛋白、抗氧化酶、药物转运蛋白和解毒因子的表达。
选择与Nrf2有直接关系的Nrf2信号通路相关基因，包括ATF4、BACH1、CREBBP、CUL3、EIF2AK3、EP300、FOS、FOSL1、GSK3B、JUN、KEAP1、MAF、MAFF、MAFG、MAFK、MAPK1、MAPK3、MAPK7、MAPK8、MAPK9、PIK3CA、PRRT2和RIT1，进行系统的泛癌分析。通过对代表33种癌症类型的11057名受试者进行Spearson相关性分析，计算Nrf2信号通路相关基因表达与肿瘤突变负担、微卫星状态、临床特征、免疫系统、癌症干性指数和药物敏感性之间的关系。采用Cox多因素回归分析和最小绝对收缩和选择算子（Lasso）回归构建肺鳞癌、乳腺癌和胃癌的预后模型。
许多Nrf2信号通路相关基因在肿瘤组织和正常组织之间存在差异表达。PIK3CA在泛癌中显示出高突变率。Nrf2信号通路相关基因的表达与肿瘤突变负担、拷贝数变异、微卫星不稳定性评分、生存率、病理分期、免疫表型、免疫评分、免疫细胞、癌症干性指数和药物敏感性显著相关。预后模型与肺鳞癌、乳腺癌和胃癌的生存率显著相关；基于预后模型的风险评分与每种癌症的临床病理特征显著相关。
该研究提供了Nrf2通路相关基因的全面泛癌概况。基于相同的Nrf2通路相关基因，为不同类型的癌症构建了不同的预后模型。
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