Ren Haitao, Wang Bing, Wang Lanni, Shi Ye, Li Ruini, Jiang Chaoyi, Feng Jingxin, Wang Jiahao, Yao Hanru, Lan Linhua, Gao Guohui, Li Liyi, Xiang Guangxin, Xu Feng, Zheng Xiaoqun
Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhengjiang, China.
School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhengjiang, China.
Commun Biol. 2025 Feb 17;8(1):251. doi: 10.1038/s42003-025-07674-z.
The correlation between persistent human cytomegalovirus (HCMV) infection and poor prognosis in colorectal cancer (CRC) patients has garnered increasing attention. UL82 is a tegument protein of HCMV, and our previous research indicated that the presence of UL82 is significantly associated with reduced overall survival in CRC patients. However, the mechanism by which UL82 affects the prognosis of CRC patients remains unclear. In this study, we investigated the role of UL82 in CRC progression through both in vitro and in vivo experiments, and revealed its downstream regulatory pathways by integrating transcriptomics, metabolomics, and proteomics. Our findings first revealed that UL82 significantly promoted CRC cell proliferation by increasing the proportion of cells in the S phase of the cell cycle. Additionally, UL82 enhanced the expression of the oncogene AGR2, while knockdown of AGR2 abolished the proliferative effect of UL82. Interestingly, UL82 interacted with the transcription factor DDX5, which transcriptionally inhibited AGR2 expression. Furthermore, this UL82-AGR2 axis promoted nucleotide metabolism in CRC cells by enhancing the levels of nucleotide synthesis enzymes DTYMK, RRM2, and TYMS. In conclusion, our study suggests that the UL82/DDX5 complex may promote nucleotide metabolism and cell cycle progression of CRC by upregulating AGR2 and UL82 may serve as a potential prognostic biomarker for CRC patients.
持续性人巨细胞病毒（HCMV）感染与结直肠癌（CRC）患者预后不良之间的相关性已受到越来越多的关注。UL82是HCMV的一种包膜蛋白，我们之前的研究表明，UL82的存在与CRC患者总生存期缩短显著相关。然而，UL82影响CRC患者预后的机制仍不清楚。在本研究中，我们通过体外和体内实验研究了UL82在CRC进展中的作用，并通过整合转录组学、代谢组学和蛋白质组学揭示了其下游调控途径。我们的研究结果首次表明，UL82通过增加细胞周期S期细胞比例显著促进CRC细胞增殖。此外，UL82增强了癌基因AGR2的表达，而敲低AGR2则消除了UL82的增殖作用。有趣的是，UL82与转录因子DDX5相互作用，后者转录抑制AGR2表达。此外，这个UL82-AGR2轴通过提高核苷酸合成酶DTYMK、RRM2和TYMS的水平促进CRC细胞中的核苷酸代谢。总之，我们的研究表明，UL82/DDX5复合物可能通过上调AGR2促进CRC的核苷酸代谢和细胞周期进程，并且UL82可能作为CRC患者潜在的预后生物标志物。
