多组学分析鉴定 PTTG1 为与免疫治疗和化疗耐药相关的预后生物标志物。

Multi-omics analysis identifies PTTG1 as a prognostic biomarker associated with immunotherapy and chemotherapy resistance.

机构信息

Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi, China.

出版信息

BMC Cancer. 2024 Oct 25;24(1):1315. doi: 10.1186/s12885-024-13060-5.

DOI:10.1186/s12885-024-13060-5

PMID:39455949

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11520140/

Abstract

BACKGROUND

Pituitary tumor-transforming gene 1 (PTTG1) is an important gene in tumour development. However, the relevance of PTTG1 in tumour prognosis, immunotherapy response, and medication sensitivity in human pan-cancer has to be determined.

METHODS

TIMER, GEPIA, the human protein atlas, GEPIA, TISCH2, and cBioportal examined the gene expression, protein expression, prognostic value, and genetic modification landscape of PTTG1 in 33 malignancies based on the TCGA cohort. The association between PTTG1 and tumour immunity, tumour microenvironment, immunotherapy response, and anticancer drug sensitivity was investigated using GSCA, TIDE, and CellMiner CDB. Molecular docking was used to validate the possible chemotherapeutic medicines for PTTG1. Additionally, siRNA-mediated knockdown was employed to confirm the probable role of PTTG1 in paclitaxel-resistant cells.

RESULTS

PTTG1 is overexpressed and associated with poor survival in most tumors. Functional enrichment study revealed that PTTG1 is involved in the cell cycle and DNA replication. A substantial connection between PTTG1 expression and immune cell infiltration points to PTTG1's possible role in the tumour microenvironment. High PTTG1 expression is associated with tumour immunotherapy resistance. The process could be connected to PTTG1, which mediates T cell exhaustion and promotes cytotoxic T lymphocyte malfunction. Furthermore, PTTG1 was found to be substantially linked with sensitivity to several anticancer medications. Suppressing PTTG1 with siRNA reduced clone formation and migration, implying that PTTG1 may play a role in paclitaxel resistance.

CONCLUSION

PTTG1 shows potential as a cancer diagnostic, prognostic, and chemosensitivity marker. Increased PTTG1 expression is linked to resistance to cancer treatment. The mechanism could be linked to PTTG1's role in promoting cytotoxic T lymphocyte dysfunction and mediating T cell exhaustion. It is feasible to consider PTTG1, which is expressed on Treg and Tprolif cells, as a new therapeutic target for overcoming immunotherapy resistance.

摘要

背景

垂体肿瘤转化基因 1（PTTG1）是肿瘤发生发展的重要基因。然而，PTTG1 在人类泛癌中的肿瘤预后、免疫治疗反应和药物敏感性的相关性尚待确定。

方法

基于 TCGA 队列，通过 TIMER、GEPIA、人类蛋白质图谱、GEPIA、TISCH2 和 cBioportal 检查了 33 种恶性肿瘤中 PTTG1 的基因表达、蛋白表达、预后价值和遗传修饰图谱。使用 GSCA、TIDE 和 CellMiner CDB 研究了 PTTG1 与肿瘤免疫、肿瘤微环境、免疫治疗反应和抗癌药物敏感性的关系。采用分子对接验证了可能针对 PTTG1 的化疗药物。此外，通过 siRNA 介导的敲低实验证实了 PTTG1 在紫杉醇耐药细胞中的可能作用。

结果

PTTG1 在大多数肿瘤中过度表达并与不良预后相关。功能富集研究表明，PTTG1 参与细胞周期和 DNA 复制。PTTG1 表达与免疫细胞浸润之间存在显著关联，提示 PTTG1 可能在肿瘤微环境中发挥作用。高 PTTG1 表达与肿瘤免疫治疗抵抗有关。这一过程可能与 PTTG1 有关，它介导 T 细胞耗竭并促进细胞毒性 T 淋巴细胞功能障碍。此外，还发现 PTTG1 与几种抗癌药物的敏感性有很大关系。用 siRNA 抑制 PTTG1 可减少克隆形成和迁移，表明 PTTG1 可能在紫杉醇耐药中发挥作用。

结论

PTTG1 具有作为癌症诊断、预后和化疗敏感性标志物的潜力。PTTG1 表达增加与癌症治疗抵抗有关。其机制可能与 PTTG1 促进细胞毒性 T 淋巴细胞功能障碍和介导 T 细胞耗竭的作用有关。考虑到 PTTG1 在 Treg 和 Tprolif 细胞上表达，可以将其作为克服免疫治疗抵抗的新治疗靶点。