Cho Miyeon, Byun Hyeji, Lee Sun Hee, Youn Sohyun, Jung Inuk, Jung Joohee, Lee Junho, Cho Hyosun, Kang Hyojeung
Vessel-Organ Interaction Research Center, Healthcare Convergence Educational Group for Infectious Disease Management, Research Institute of Pharmaceutical Science, College of Pharmacy, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea.
Department of Computer Science and Engineering, Kyungpook National University, Daegu, Korea.
Gastric Cancer. 2025 Jun 12. doi: 10.1007/s10120-025-01626-6.
Our Kaplan-Meier analysis reveals that gastric cancer patients with high androgen receptor (AR) expression demonstrate poorer survival outcomes compared to those with low AR expression, particularly in patients with characteristics typical of EBV-positive gastric cancer. However, the molecular mechanisms driving this seemingly contradictory relationship have remained poorly understood, as our experimental findings suggest AR signaling actually suppresses tumor growth in EBVaGC.
The study utilized AR-positive EBV-infected gastric cancer cell lines treated with dihydrotestosterone (DHT) to investigate molecular pathways. Comprehensive analyses included examination of apoptosis, miRNA expression, signaling pathways, DNA methylation patterns, and viral gene expression. In vivo validation was performed using xenograft models with MKN1-EBV and SNU719 cells to assess tumor growth and immune response.
DHT treatment triggered early apoptosis through upregulation of pro-apoptotic miRNAs, particularly miR-204-5p, while activating the PI3K-Akt pathway and enhancing DNA damage response through increased phosphorylation of key proteins. The treatment reduced DNMT3A expression, leading to genome-wide DNA demethylation and increased expression of both lytic (BZLF1) and latent (EBNA1, LMP1) EBV genes. Xenograft studies confirmed these findings, showing reduced tumor growth, increased lymphocyte infiltration, and enhanced viral gene expression specifically in AR-positive tumors.
The study reveals that AR signaling suppresses EBV-positive gastric cancer by modulating both cellular apoptosis and EBV reactivation through epigenetic mechanisms. These findings suggest that AR agonists might have therapeutic potential in treating AR-positive EBV-associated gastric cancer.
我们的Kaplan-Meier分析显示，与雄激素受体（AR）低表达的胃癌患者相比，AR高表达的胃癌患者生存结局更差，尤其是在具有EBV阳性胃癌典型特征的患者中。然而，驱动这种看似矛盾关系的分子机制仍不清楚，因为我们的实验结果表明AR信号实际上抑制了EBVaGC中的肿瘤生长。
该研究利用用二氢睾酮（DHT）处理的AR阳性EBV感染的胃癌细胞系来研究分子途径。综合分析包括对细胞凋亡、miRNA表达、信号通路、DNA甲基化模式和病毒基因表达的检测。使用MKN1-EBV和SNU719细胞的异种移植模型进行体内验证，以评估肿瘤生长和免疫反应。
DHT处理通过上调促凋亡miRNA，特别是miR-204-5p触发早期细胞凋亡，同时激活PI3K-Akt途径并通过增加关键蛋白的磷酸化增强DNA损伤反应。该处理降低了DNMT3A的表达，导致全基因组DNA去甲基化以及裂解性（BZLF1）和潜伏性（EBNA1、LMP1）EBV基因的表达增加。异种移植研究证实了这些发现，显示肿瘤生长减少、淋巴细胞浸润增加以及病毒基因表达增强，特别是在AR阳性肿瘤中。
该研究表明，AR信号通过表观遗传机制调节细胞凋亡和EBV再激活来抑制EBV阳性胃癌。这些发现表明AR激动剂可能在治疗AR阳性EBV相关胃癌方面具有治疗潜力。
