Liao Pan, Han Zhaoli, Yan Bo, Chen Fanglian, Lei Ping
The School of Medicine, Nankai University 94 Weijin Road, Tianjin 300071, China; Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China.
Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Int J Biol Macromol. 2025 Aug;319(Pt 4):145707. doi: 10.1016/j.ijbiomac.2025.145707. Epub 2025 Jul 1.
The thymidine phosphorylase (TYMP) gene encodes a pivotal enzyme involved in nucleoside metabolism, playing a critical role in the processing of chemotherapeutic agents. Despite its recognized importance, the influence of TYMP on tumor immunology and clinical outcomes remains largely unexplored. This study sought to elucidate the roles and regulatory pathways of TYMP across a spectrum of cancers and whether TYMP is related to DNA damage repair, thereby promoting stem cell maintenance, chemotherapy resistance and immunosuppression. Utilizing pan-cancer bulk sequencing and digital platforms, the study investigated the impact of TYMP on patient outcomes, genomic instability, cancer stemness, DNA repair, and immune cell dynamics. Moreover, single-cell datasets of TISCH, spatial transcriptomic data of SpatialDB, and multiple fluorescence staining were used to validate the association between TYMP expression and macrophages. In vitro viability (trypan blue), wound healing, Transwell, Cell cycle and M1 macrophage infiltration assays were performed to determine the biological functions of TYMP in Kidney renal clear cell carcinoma (KIRC) cells. Tools such as ROCplotter and cMap were employed to evaluate treatment responses and identify compounds targeting TYMP, while PDB and Autodock Vina facilitated structural modeling and binding simulations. TYMP was an oncogene in many cancer types. High TYMP was associated with lower genome stability and high expression of mismatch repair genes, stemness, homologous repair gene signature. Also, immune checkpoint CD276 was positively relevant to TYMP. Subsequently, we validated TYMP as the macrophage marker and showed its connection with other immunosuppressive cells and CD8+ T-cell depression. In vitro experiments showed that TYMP promoted migration, and invasion of KIRC cells and recruited the M2 macrophage to KIRC cells. Finally, potential TYMP -targeted drugs were screened out and docked to TYMP protein. TYMP was a novel oncogene, and it correlated with immunosuppression and DNA repair. TYMP was highly associated with immune checkpoint CD276 and was an macrophage biomarker in many cancers. This study will reveal TYMP's roles in pan-cancer and its potential as a novel therapeutic target, especially KIRC.
胸苷磷酸化酶（TYMP）基因编码一种参与核苷代谢的关键酶，在化疗药物的处理过程中发挥着关键作用。尽管其重要性已得到认可，但TYMP对肿瘤免疫学和临床结果的影响在很大程度上仍未得到探索。本研究旨在阐明TYMP在一系列癌症中的作用和调控途径，以及TYMP是否与DNA损伤修复相关，从而促进干细胞维持、化疗耐药性和免疫抑制。该研究利用泛癌批量测序和数字平台，调查了TYMP对患者预后、基因组不稳定性、癌症干性、DNA修复和免疫细胞动态的影响。此外，还使用了TISCH的单细胞数据集、SpatialDB的空间转录组数据和多重荧光染色来验证TYMP表达与巨噬细胞之间的关联。进行了体外活力（台盼蓝）、伤口愈合、Transwell、细胞周期和M1巨噬细胞浸润试验，以确定TYMP在肾透明细胞癌（KIRC）细胞中的生物学功能。使用ROCplotter和cMap等工具评估治疗反应并鉴定靶向TYMP的化合物，而PDB和Autodock Vina则有助于进行结构建模和结合模拟。TYMP在许多癌症类型中是一种癌基因。高TYMP与较低的基因组稳定性以及错配修复基因、干性、同源修复基因特征的高表达相关。此外，免疫检查点CD276与TYMP呈正相关。随后，我们验证了TYMP作为巨噬细胞标志物，并展示了其与其他免疫抑制细胞和CD8 + T细胞抑制的联系。体外实验表明，TYMP促进了KIRC细胞的迁移和侵袭，并将M2巨噬细胞募集到KIRC细胞。最后，筛选出潜在的靶向TYMP的药物并将其与TYMP蛋白对接。TYMP是一种新型癌基因，与免疫抑制和DNA修复相关。TYMP与免疫检查点CD276高度相关，并且在许多癌症中是巨噬细胞生物标志物。本研究将揭示TYMP在泛癌中的作用及其作为新型治疗靶点的潜力，尤其是在KIRC中。
