基于生物信息学分析MRPS35表达与胃癌预后和肿瘤微环境的关系

The Relationship between Expression of MRPS35 and Prognosis and Tumor Microenvironment in Gastric Cancer Based on Bioinformatics Analysis

摘要: 目的：探讨线粒体核糖体蛋白S35 (MRPS35)在胃癌中的表达及其与胃癌临床病理特征、预后和免疫微环境之间的关系。方法：采用TIMER、GEPIA、TCGA、GTEx、Kaplan-Meier Plotter、STRING数据库和GeneMANIA数据库探讨胃癌中MRPS35的表达模式、预后和基因–蛋白质相互作用网络。进一步应用UACLAN数据库分析MRPS35在胃癌亚型中的表达，随后利用CCLE数据库分析MRPS35在胃癌细胞系中的表达情况。通过cBioportal和UACLAN探讨了MRPS35遗传学改变和甲基化水平在胃癌中的意义。通过基因本体(GO)和京都基因与基因组百科全书(KEGG)分析提示MRPS35在胃癌中可能参与的功能和信号通路。最后，开发了一种基于MRPS35的预后模型，通过校准曲线和时间依赖性受试者工作特征(ROC)曲线的曲线下面积(AUC)进行评估。结果：数据库证实了MRPS35在胃癌组织中高表达，且与临床预后呈负相关(P < 0.05)，MRPS35在不同细胞系中表达水平也不相同。同时，MRPS35的基因突变、DNA甲基化、异质性影响抗肿瘤免疫作用，也与免疫细胞息息相关。KEGG富集结果提示MRPS35的高表达与细胞增殖和免疫应答相关的信号通路有关。通过分析MRPS35表达与胃癌临床病理特征的相关性提示：MRPS35高表达与肿瘤分化程度(G分级)、淋巴结转移(N分期)和肿瘤分期(S分期)显著相关(P < 0.001, P < 0.001, P = 0.007)。此外，Cox多因素回归分析将MRPS35确定为胃癌患者预后的关键影响因素(P = 0.031)。预后模型总体C-index为0.734 (95% CI, 0.693~0.775, P = 6.9e−29)，有望成为预测MPRS35胃癌患者生存的模型。结论：MRPS35在胃癌中高表达，并且与胃癌患者的预后、各种类型的免疫细胞及免疫应答相关，在未来是一个潜在的预后标志物及治疗靶点。

Abstract: Objective: To investigate the expression of mitochondrial ribosomal protein S35 (MRPS35) in gastric cancer and its relationship with clinicopathologic features, prognosis and immune microenvironment of gastric cancer. Methods: TIMER, GEPIA, TCGA, GTEx, Kaplan-Meier Plotter, STRING database and GeneMANIA database were used to explore the expression pattern, prognosis and gene-protein interaction network of MRPS35 in gastric cancer. The UACLAN database was further applied to analyze the expression of MRPS35 in gastric cancer subtypes, followed by the CCLE database to analyze the expression of MRPS35 in gastric cancer cell lines. The significance of MRPS35 genetic alterations and methylation levels in gastric cancer was explored by cBioportal and UACLAN. The possible functions and signaling pathways involved in MRPS35 in gastric cancer were suggested by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Finally, a prognostic model based on MRPS35 was developed and evaluated by calibration curves and area under the curve (AUC) of time-dependent subject operating characteristic (ROC) curves. Results: The database confirmed that MRPS35 was highly expressed in gastric cancer tissues and negatively correlated with clinical prognosis (P < 0.05), and the expression level of MRPS35 varied in different cell lines. Meanwhile, the gene mutation, DNA methylation, and heterogeneity of MRPS35 affected the anti-tumor immune effects and were also closely related to immune cells. KEGG enrichment results suggested that the high expression of MRPS35 was associated with signaling pathways related to cell proliferation and immune response. By analyzing the correlation between MRPS35 expression and clinicopathological features of gastric cancer, it was suggested that the high expression of MRPS35 was significantly correlated with the degree of tumor differentiation (G grade), lymph node metastasis (N stage) and tumor stage (S stage) (P < 0.001, P < 0.001, P = 0.007). In addition, Cox multifactorial regression analysis identified MRPS35 as a key influencing factor in the prognosis of gastric cancer patients (P = 0.031). The overall C-index of the prognostic model was 0.734 (95% CI, 0.693~0.775, P = 6.9e−29), which is expected to be a predictive model for the survival of patients with gastric cancer with MRPS35. Conclusion: MRPS35 is highly expressed in gastric cancer and is associated with the prognosis of gastric cancer patients, various types of immune cells and immune responses, and is a potential prognostic marker and therapeutic target in the future.