MTA2 在泛癌和肝细胞癌药物筛选中的预后、免疫学和突变分析,Biomolecules

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MTA2 在泛癌和肝细胞癌药物筛选中的预后、免疫学和突变分析
Biomolecules ( IF 4.8 ) Pub Date : 2023-05-24 , DOI: 10.3390/biom13060883
Xueshan Huang ₁ , Jingyi Tan _{2,

3} , Mei Chen ₁ , Weirang Zheng ₁ , Shanyang Zou ₁ , Xiaoxia Ye ₃ , Yutong Li ₁ , Minhua Wu ₃

Affiliation

背景：转移相关蛋白 2 (MTA2) 是转移相关转录调节因子家族的成员，是核小体重塑和组蛋白脱乙酰化复合物的核心成分。尽管越来越多的证据表明 MTA2 在某些癌症的肿瘤发生中发挥着至关重要的作用，但迄今为止还没有系统的 MTA2 泛癌分析。因此，我们研究的目的是探讨MTA2在33种癌症类型中的预后价值，并探讨其潜在的免疫功能。方法：通过综合利用 TCGA、GTEx、GEO、UCSC xena、cBioPortal、comPPI、GeneMANIA、TCIA、MSigDB 和 PDB 数据库，我们应用各种生物信息学方法来研究 MTA2 的潜在作用，包括分析 MTA2 与MSI、预后、基因突变、以及不同肿瘤中免疫细胞的浸润情况。我们在 TCGA-LIHC 中构建列线图，对肝细胞癌 (HCC) 中的 MTA2 进行单细胞测序 (scRNA-seq) 分析，并筛选治疗 HCC 的药物。最后，进行免疫组化实验来验证MTA2在HCC中的表达和预后价值。采用体外实验观察MK-886对HCC细胞系HepG2的生长抑制作用。结果：结果提示MTA2在大多数癌症中高表达，且MTA2表达与不同癌症的预后相关。此外，MTA2 表达与 12 种癌症类型中的肿瘤突变负荷 (TMB) 以及 8 种癌症类型中的 MSI 相关。免疫测定表明，MTA2 与 HCC 中活化的记忆 CD4 T 细胞和 M0 巨噬细胞浸润水平呈正相关。基于GEO数据集的ScRNA-seq分析发现MTA2在HCC的T细胞中显着表达。最后采用eXtreme Sum（Xsum）算法筛选抗肿瘤药物MK-886，并利用分子对接技术揭示MK-886与MTA2蛋白的结合能力。结果表明它们之间具有良好的结合位点，通过π-烷基和烷基相互作用力相互结合。免疫组织化学实验表明，MTA2蛋白在HCC中高表达，并且MTA2高表达与HCC患者的较差生存相关。MK-886 以剂量依赖性方式显着抑制 HepG2 细胞的增殖并诱导细胞死亡。结论：我们的研究表明，MTA2 在肿瘤进展和肿瘤免疫中发挥着至关重要的作用，可作为多种恶性肿瘤的预后标志物。MK-886 可能是治疗 HCC 的强效药物。

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Prognostic, Immunological, and Mutational Analysis of MTA2 in Pan-Cancer and Drug Screening for Hepatocellular Carcinoma

Background: Metastasis-associated protein 2 (MTA2) is a member of the metastasis-associated transcriptional regulator family and is a core component of the nucleosome remodeling and histone deacetylation complex. Despite growing evidence that MTA2 plays a crucial role in the tumorigenesis of certain cancers, no systematic pan-cancer analysis of MTA2 is available to date. Therefore, the aim of our study is to explore the prognostic value of MTA2 in 33 cancer types and to investigate its potential immune function. Methods: by comprehensive use of databases from TCGA, GTEx, GEO, UCSC xena, cBioPortal, comPPI, GeneMANIA, TCIA, MSigDB, and PDB, we applied various bioinformatics approaches to investigate the potential role of MTA2, including analyzing the association of MTA2 with MSI, prognosis, gene mutation, and immune cell infiltration in different tumors. We constructed a nomogram in TCGA-LIHC, performed single-cell sequencing (scRNA-seq) analysis of MTA2 in hepatocellular carcinoma (HCC), and screened drugs for the treatment of HCC. Finally, immunohistochemical experiments were performed to verify the expression and prognostic value of MTA2 in HCC. In vitro experiments were employed to observe the growth inhibition effects of MK-886 on the HCC cell line HepG2. Results: The results suggested that MTA2 was highly expressed in most cancers, and MTA2 expression was associated with the prognosis of different cancers. In addition, MTA2 expression was associated with Tumor Mutation Burden (TMB) in 12 cancer types and MSI in 8 cancer types. Immunoassays indicated that MTA2 positively correlated with activated memory CD4 T cells and M0 macrophage infiltration levels in HCC. ScRNA-seq analysis based on the GEO dataset discovered that MTA2 was significantly expressed in T cells in HCC. Finally, the eXtreme Sum (Xsum) algorithm was used to screen the antitumor drug MK-886, and the molecular docking technique was utilized to reveal the binding capacity between MK-886 and the MTA2 protein. The results demonstrated excellent binding sites between them, which bind to each other through Π-alkyl and alkyl interaction forces. An immunohistochemistry experiment showed that MTA2 protein was highly expressed in HCC, and high MTA2 expression was associated with poor survival in HCC patients. MK-886 significantly inhibited the proliferation and induced cell death of HepG2 cells in a dose-dependent manner. Conclusions: Our study demonstrated that MTA2 plays crucial roles in tumor progression and tumor immunity, and it could be used as a prognostic marker for various malignancies. MK-886 might be a powerful drug for HCC.

更新日期：2023-05-24

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