PTGER4,也称为前列腺素E受体4(EP4),是一种编码前列腺素E2(PGE2)受体的基因。PGE2是一种重要的生物活性脂质,参与调节多种生物学过程,包括免疫调节、骨代谢、血管稳态、肿瘤发生和炎症反应。EP4受体是PGE2信号传导的关键组成部分,其功能异常与多种疾病的发生和发展密切相关。
PTGER4基因在骨代谢中发挥着重要作用。研究显示,PTGER4基因变异与类风湿性关节炎(RA)患者放射学关节损伤的风险增加相关[1]。此外,PTGER4基因还与胃癌的易感性相关,其中rs10036575变异与胃癌的易感性增加相关[2]。此外,PTGER4基因还与肝细胞癌的免疫微环境相关,其中SPP1基因通过PTGER4与CD44相互作用,介导肝癌细胞和巨噬细胞之间的串扰[6]。
PTGER4基因在骨代谢中的作用还体现在其与感觉神经对骨稳态的调节中。研究表明,PGE2由成骨细胞分泌,激活感觉神经中的EP4受体,通过抑制交感神经活动来调节骨形成[3]。此外,PTGER4基因还参与调节间充质干细胞(MSC)的谱系承诺,通过调节交感神经张力来影响骨量积累[4]。研究还发现,PTGER4基因与血管稳态相关,血管平滑肌细胞(VSMC)特异性EP4基因缺失加剧了血管炎症和血压升高,导致血管重构[5]。
PTGER4基因还与肿瘤免疫治疗相关。研究表明,EP4受体在前列腺癌的免疫微环境中表达,并参与调节肿瘤免疫反应。新型EP4拮抗剂YY001与抗PD-1抗体联合使用,可增强CD8+ T细胞的浸润和活性,降低MDSC的比例和免疫抑制功能,从而提高前列腺癌的免疫治疗效果[7]。此外,PTGER4基因的DNA甲基化水平可作为肺癌检测和鉴别诊断的潜在生物标志物[8]。
综上所述,PTGER4基因在多种生物学过程中发挥着重要作用,包括骨代谢、血管稳态、肿瘤发生和免疫反应。PTGER4基因的变异与多种疾病的发生和发展密切相关,包括类风湿性关节炎、胃癌、肝细胞癌和前列腺癌。PTGER4基因的研究有助于深入理解其生物学功能和疾病发生机制,为疾病的治疗和预防提供新的思路和策略。
参考文献:
1. Rodriguez-Rodriguez, Luis, Ivorra-Cortes, Jose, Carmona, F David, González-Álvaro, Isidoro, Fernandez-Gutiérrez, Benjamín. 2015. PTGER4 gene variant rs76523431 is a candidate risk factor for radiological joint damage in rheumatoid arthritis patients: a genetic study of six cohorts. In Arthritis research & therapy, 17, 306. doi:10.1186/s13075-015-0830-z. https://pubmed.ncbi.nlm.nih.gov/26538147/
2. Yu, Shuyong, Tu, Ruisha, Chen, Zhaowei, Zhang, Ronglin, Li, Yini. 2023. Association of PTGER4 and PRKAA1 genetic polymorphisms with gastric cancer. In BMC medical genomics, 16, 209. doi:10.1186/s12920-023-01645-1. https://pubmed.ncbi.nlm.nih.gov/37670284/
3. Chen, Hao, Hu, Bo, Lv, Xiao, Yang, Huilin, Cao, Xu. 2019. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. In Nature communications, 10, 181. doi:10.1038/s41467-018-08097-7. https://pubmed.ncbi.nlm.nih.gov/30643142/
4. Hu, Bo, Lv, Xiao, Chen, Hao, Yuan, Wen, Cao, Xu. . Sensory nerves regulate mesenchymal stromal cell lineage commitment by tuning sympathetic tones. In The Journal of clinical investigation, 130, 3483-3498. doi:10.1172/JCI131554. https://pubmed.ncbi.nlm.nih.gov/32191640/
5. Xu, Hu, Du, Shengnan, Fang, Bingying, Gustafsson, Jan-Åke, Guan, Youfei. 2019. VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure. In Proceedings of the National Academy of Sciences of the United States of America, 116, 8457-8462. doi:10.1073/pnas.1902119116. https://pubmed.ncbi.nlm.nih.gov/30948641/
6. Liu, Lulu, Zhang, Ruyi, Deng, Jingwen, Zheng, Yi, Bao, Xuanwen. 2021. Construction of TME and Identification of crosstalk between malignant cells and macrophages by SPP1 in hepatocellular carcinoma. In Cancer immunology, immunotherapy : CII, 71, 121-136. doi:10.1007/s00262-021-02967-8. https://pubmed.ncbi.nlm.nih.gov/34028567/
7. Peng, Shihong, Hu, Pan, Xiao, Yu-Tian, Liu, Mingyao, Ren, Shancheng. 2021. Single-Cell Analysis Reveals EP4 as a Target for Restoring T-Cell Infiltration and Sensitizing Prostate Cancer to Immunotherapy. In Clinical cancer research : an official journal of the American Association for Cancer Research, 28, 552-567. doi:10.1158/1078-0432.CCR-21-0299. https://pubmed.ncbi.nlm.nih.gov/34740924/
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