Qi Jia, Wu Wenxuan, Chen Jing, Han Xiaying, Hao Zhixing, Han Yaxuan, Xu Yewei, Lai Jun, Chen Jian
Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, Zhejiang, China.
Department of Cardiology Guangdong Second Provincial General Hospital, Guangzhou, 510000, Guangdong, China.
Heliyon. 2024 Mar 17;10(6):e28307. doi: 10.1016/j.heliyon.2024.e28307. eCollection 2024 Mar 30.
Gastric Cancer (GC) refers to a prevalent malignant cancer accompanied by a weak prognosis. The APOBEC3 family genes and lncRNAs are linked with cancer progression. Nevertheless, there is still a scarcity of data concerning the prognostic value of APOBEC3-related lncRNAs in GC.
We extracted the data from GC samples, including transcriptome as well as clinical data, obtained from the TCGA database. Then, we screened for lncRNAs that were correlated with the APOBEC3 family genes and constructed an APOBEC3-related lncRNA prognostic signature (LPS) by utilizing univariate Cox and lasso regression analysis. Furthermore, we validated our constructed signature and evaluated it thoroughly, including analysis of its function, immunity, mutations, and clinical applications via multiple methods, including Metascape, GSEA, and analyses including TIC and TME, immune checkpoints, CNV and SNPs, Kaplan-Meier survival curves, nomogram, decision tree and drug prediction analysis. Finally, we overexpressed LINC01094 to evaluate the impacts on the proliferation as well as migration with regards to KATO-2 cells.
We selected eight lncRNAs for our APOBEC3-related LPS, which is demonstrated as a valuable tool in predicting the individual GC patients' prognosis. Subsequently, we segregated the samples into subgroups of high-as well as low-risk relying on the risk score with regards to APOBEC3-related LPS. By performing functional analysis, we have shown that immune-as well as tumor-related pathways were enriched in high- and low-risk GC patients. Furthermore, immune analysis revealed a robust correlation between the APOBEC3-related LPS and immunity. We found that immune checkpoints were significantly associated with the APOBEC3-related LPS and were greatly exhibited in GC tumor and high-risk samples. Mutational analysis suggested that the mutational rate was greater in low-risk samples. Furthermore, we predicted small molecular drugs displayed greater sensitivity in patients categorized as high-risk. Moreover, the immune response was also better in high-risk patients. Of these drugs, dasatinib was significant in both methods and might be considered a potential novel drug for treating high-risk GC patients. Finally, we found that LINC01094 has the potential to enhance the migration, proliferation as well as inhibit apoptosis of KATO-2 in GC cells. And Dasatinib has an inhibitory effect on the migration as well as proliferation in GC cells.
We created a novel APOBEC3-related LPS in predicting the prognosis with regards to individual GC patients. Importantly, this APOBEC3-related LPS was closely associated with immunity and might guide clinical treatment.
胃癌（GC）是一种常见的恶性肿瘤，预后较差。载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC3）家族基因和长链非编码RNA（lncRNAs）与癌症进展相关。然而，关于APOBEC3相关lncRNAs在胃癌中的预后价值的数据仍然匮乏。
我们从癌症基因组图谱（TCGA）数据库获得的胃癌样本中提取数据，包括转录组数据和临床数据。然后，我们筛选与APOBEC3家族基因相关的lncRNAs，并利用单变量Cox和套索回归分析构建APOBEC3相关lncRNA预后特征（LPS）。此外，我们验证了构建的特征并进行了全面评估，包括通过多种方法分析其功能、免疫、突变和临床应用，如Metascape、基因集富集分析（GSEA）以及肿瘤免疫细胞组成（TIC）和肿瘤微环境（TME）分析、免疫检查点分析、拷贝数变异（CNV）和单核苷酸多态性（SNP）分析、Kaplan-Meier生存曲线分析、列线图分析、决策树分析和药物预测分析。最后，我们过表达LINC0109去评估其对KATO-2细胞增殖和迁移的影响。
我们为APOBEC3相关LPS选择了8个lncRNAs，它被证明是预测个体胃癌患者预后的有价值工具。随后，我们根据APOBEC3相关LPS的风险评分将样本分为高风险和低风险亚组。通过功能分析，我们发现免疫和肿瘤相关通路在高风险和低风险胃癌患者中均有富集。此外，免疫分析显示APOBEC3相关LPS与免疫之间存在强相关性。我们发现免疫检查点与APOBEC3相关LPS显著相关，并且在胃癌肿瘤和高风险样本中大量表达。突变分析表明低风险样本中的突变率更高。此外，我们预测小分子药物在高风险患者中表现出更高的敏感性。此外，高风险患者的免疫反应也更好。在这些药物中，达沙替尼在两种方法中均有显著作用，可能被认为是治疗高风险胃癌患者的潜在新型药物。最后，我们发现LINC01094有可能增强胃癌细胞中KATO-2的迁移、增殖并抑制其凋亡。并且达沙替尼对胃癌细胞的迁移和增殖有抑制作用。
我们创建了一种新型的APOBEC3相关LPS来预测个体胃癌患者的预后。重要的是，这种APOBEC3相关LPS与免疫密切相关，可能指导临床治疗。
