Table_1_Prognostic Value and Immunological Role of MORF4-Related Gene-Binding Protein in Human Cancers.docx

MORF4-related gene-binding protein (MRGBP) is the subunit of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. Much of the research indicated an oncogenic role of MRGBP in the development of cancers. However, it is still unknown the role MRGBP plays in human cancers, which deserves further exploration. In this research, the expression profile, prognostic value of MRGBP, and the relationship between MRGBP and immune infiltration were explored in 33 types of cancer. The differences in MRGBP expression in tumor and normal tissues were explored using data from The Cancer Genome Atlas, Gene Expression Omnibus and ONCOMINE. Analysis of the association between MRGBP and prognosis using Kaplan-Meier survival curve and COX analysis. The data of Tumor mutational burden (TMB), microsatellite instability (MSI) from TCGA. The relationship Between MRGBP expression and immunity was analyzed using the ESTIMATE algorithm and CIBERSORT. Furthermore, we explored MRGBP expression and the relationship between MRGBP expression and macrophage infiltration using immunohistochemical analysis in lower grade glioma (LGG). Our results revealed that MRGBP was highly expressed in most cancer tissues compared with normal tissues. Tumors with increased MRGBP expression had a high clinicopathologic stage and poor prognosis. The expression of MRGBP was closely related to the TMB, MSI. We also found a significant negative correlation between MRGBP expression and stromal scores and immune scores in various types of cancer. Furthermore, MRGBP expression was associated with a variety of immune cells including B cells, NK cells, T cells, and macrophages. LGG and LIHC was selected as representative cancer types for further study, the results of immunohistochemistry indicated that the protein levels of MRGBP were significantly elevated in tumor tissues. Moreover, our LIHC data analysis showed that patients with high MRGBP expression were associated with short survival rates and MRGBP was a risk factor to determine OS. Immunohistochemistry also confirmed that M0 macrophage infiltration in the MRGBP-high group significantly increased. In conclusion, these results reveal that MRGBP can serve as a potential prognostic biomarker and it plays an important role in tumor immune infiltration in various tumors, especially in LGG and LIHC.

MORF4相关基因结合蛋白（MRGBP）是NuA4组蛋白乙酰转移酶复合物（NuA4 histone acetyltransferase complex）的亚基，该复合物主要通过对核小体组蛋白H4与H2A进行乙酰化修饰，参与特定基因的转录激活。诸多研究表明MRGBP在癌症发生发展中发挥致癌作用，但其在人类癌症中的具体功能仍未明确，亟需进一步探索。
本研究针对33种癌症，系统探究了MRGBP的表达谱、预后价值以及其与免疫浸润的关联。研究借助癌症基因组图谱（The Cancer Genome Atlas, TCGA）、基因表达汇编（Gene Expression Omnibus, GEO）及ONCOMINE数据库的数据，分析了MRGBP在肿瘤组织与正常组织中的表达差异；通过Kaplan-Meier生存曲线与COX回归分析，解析了MRGBP表达与患者预后的相关性；从TCGA数据库获取肿瘤突变负荷（Tumor mutational burden, TMB）与微卫星不稳定性（microsatellite instability, MSI）数据，采用ESTIMATE算法与CIBERSORT工具分析了MRGBP表达与免疫状态的关联。此外，本研究还通过免疫组化分析，在低级别胶质瘤（lower grade glioma, LGG）中探究了MRGBP的表达水平及其与巨噬细胞浸润的关系。
研究结果显示，相较于正常组织，MRGBP在多数癌症组织中呈高表达状态；MRGBP高表达的肿瘤往往伴随较高的临床病理分期与较差的预后。MRGBP的表达水平与TMB、MSI显著相关。此外，MRGBP表达与多种癌症中的间质评分及免疫评分呈显著负相关。MRGBP的表达还与B细胞、NK细胞、T细胞及巨噬细胞等多种免疫细胞的浸润密切相关。
本研究选取低级别胶质瘤（LGG）与肝细胞癌（Liver Hepatocellular Carcinoma, LIHC）作为代表性癌种开展深入分析，免疫组化结果证实MRGBP蛋白在肿瘤组织中显著高表达。针对LIHC的数据分析显示，MRGBP高表达患者的总生存期（Overall Survival, OS）更短，MRGBP可作为判断OS的风险因子。免疫组化结果同样证实，MRGBP高表达组的M0巨噬细胞浸润程度显著升高。
综上，本研究结果表明MRGBP可作为潜在的预后生物标志物，在多种肿瘤的肿瘤免疫浸润过程中发挥重要作用，尤其在LGG与LIHC中表现显著。