Sun Chenxi, Liu Xu, Liu Tiantian, Fan Chenliu, Jiang Yang, Li Binggen, Yuan Huiyang, Zheng Chengyun, Xu Dawei
Department of Hematology, The Second Hospital of Shandong University, Jinan, China.
Department of Pathology, Qilu Hospital of Shandong University, Jinan, China.
Front Cell Dev Biol. 2025 May 19;13:1592135. doi: 10.3389/fcell.2025.1592135. eCollection 2025.
Telomerase activation is essential to malignant transformation and progression including uterine corpus endometrial carcinoma (UCEC), while telomerase co-factor DKC1-mediated RNA pseudouridylation is required for functional telomerase by stabilizing telomerase RNA component (TERC) and its upregulation occurs in many cancers. Surprisingly, there is only one publication studying DKC1 in UCEC, which shows its significant downregulation.
DKC1 expression, its role in the UCEC molecular pathogenesis and clinical implications were comprehensively investigated.
Thirty UCEC patients were recruited to determine DKC1 expression in both tumors and non-tumorous endometrial tissues (NT) using immunohistochemistry. Four UCEC cohorts from TCGA and GSE datasets were analyzed for DKC1 expression and its impacts on clinic-pathological, molecular, genomic and immune landscapes.
Immunohistochemistry analyses showed significantly increased DKC1 expression in UCEC tumors than in NTs and its highest level was observed in high-grade tumors. For the TCGA cohort, DKC1 mRNA and protein levels increased significantly in tumors compared with that in NTs. DKC1 mRNA levels positively correlated with TERC and telomerase activity. Higher DKC1 expression predicted shorter patient overall and progression-free survival. DKC1 copy number alterations were frequent in UCEC tumors. Estrogen treatment of UCEC cells upregulated DKC1 expression while medroxyprogesterone inhibited its expression. DKC1-high UCEC tumors exhibited hyperproliferation, increased stemness and epithelial-mesenchymal transition, accompanied by significantly higher aneuploid, homologous recombination deficiency and micro-satellite instable scores, and higher frequencies of cancer driver aberrations. Lower immune scores were observed in DKC1-high tumors as assessed by ESTIMATE algorithm. Tumor Immune Dysfunction and Exclusion (TIDE) analyses revealed robustly higher TIDE scores featured with T Cell exclusion in DKC1-high tumors, and consistently, the diminished trafficking of immune cells into tumor tissues and substantial declines in immune cell infiltration were shown in these tumors. Moreover, DKC1-high tumors exhibited poor response to immune checkpoint inhibitor (ICI)-based immunotherapy. These observations were validated by the findings obtained from other datasets.
The present findings unravel genomic alteration- and sex hormone-mediated dysregulation of the telomerase cofactor DKC1 in UCEC tumors, and its upregulation participates actively in the UCEC pathogenesis through tumor-intrinsic and extrinsic mechanisms. DKC1 assessment is useful for patient prognostication and personalized interventions.
端粒酶激活对于包括子宫内膜癌（UCEC）在内的恶性转化和进展至关重要，而端粒酶辅助因子DKC1介导的RNA假尿苷化通过稳定端粒酶RNA组分（TERC）对功能性端粒酶是必需的，并且其上调发生在许多癌症中。令人惊讶的是，仅有一篇关于UCEC中DKC1的研究报道，该报道显示其显著下调。
全面研究DKC1的表达、其在UCEC分子发病机制中的作用及临床意义。
招募30例UCEC患者，采用免疫组织化学法检测肿瘤组织和非肿瘤子宫内膜组织（NT）中DKC1的表达。分析来自TCGA和GSE数据集的4个UCEC队列中DKC1的表达及其对临床病理、分子、基因组和免疫格局的影响。
免疫组织化学分析显示，UCEC肿瘤组织中DKC1的表达显著高于NT组织，且在高级别肿瘤中观察到其表达水平最高。对于TCGA队列，与NT组织相比，肿瘤组织中DKC1的mRNA和蛋白水平显著升高。DKC1的mRNA水平与TERC和端粒酶活性呈正相关。较高的DKC1表达预示患者总生存期和无进展生存期较短。UCEC肿瘤中DKC1拷贝数改变频繁。雌激素处理UCEC细胞可上调DKC1表达，而甲羟孕酮则抑制其表达。DKC1高表达的UCEC肿瘤表现出过度增殖、干性增加和上皮-间质转化增加，同时伴有明显更高的非整倍体、同源重组缺陷和微卫星不稳定评分，以及更高频率的癌症驱动畸变。通过ESTIMATE算法评估，DKC1高表达肿瘤的免疫评分较低。肿瘤免疫功能障碍与排除（TIDE）分析显示，DKC1高表达肿瘤的TIDE评分显著更高，其特征为T细胞排除，并且这些肿瘤中免疫细胞向肿瘤组织的迁移减少以及免疫细胞浸润显著下降。此外，DKC1高表达肿瘤对基于免疫检查点抑制剂（ICI）的免疫治疗反应较差。这些观察结果在其他数据集获得的结果中得到了验证。
本研究结果揭示了UCEC肿瘤中端粒酶辅助因子DKC1的基因组改变和性激素介导的失调，并且其上调通过肿瘤内在和外在机制积极参与UCEC发病过程。DKC1评估对患者预后和个性化干预有用。
