Zhang Qiang, Tian HengJin, Ge Kunpeng, Wang FeiFan, Gao PeiYao, Chen AMin, Wang Lulu, Zhao YanMing, Lian Chaoqun, Wang FengChao
Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, Bengbu Medical University, Bengbu, China.
Front Oncol. 2024 Dec 24;14:1496050. doi: 10.3389/fonc.2024.1496050. eCollection 2024.
Prostaglandin D2 (PGD2) inhibits the development of different malignant tumors; however, the underlying mechanism of inhibiting tumor development is not yet clear. This study aimed to elucidate how PGD2 inhibits the stemness of gastric cancer stem cells (GCSCs) autophagy and its underlying molecular mechanism to provide a theoretical basis for the treatment of gastric cancer.
In this study, GCSCs were enriched by serum-free incubation. Furthermore, the effects of PGD2 and PGD2 receptor (PTGDR2) on autophagy were detected by Western blotting, immunofluorescence analysis, and transmission electron microscopy. Moreover, the ATG4B ubiquitination levels were assessed immunoprecipitation and other methods.
The results indicated that PGD2 induced LC3I/LC3II conversion in GCSCs to activate autophagy, while PGD2 promoted the expression of PTGDR2, thereby further activating autophagy. Furthermore, PTGDR2 competes with ATG4B for binding with E3 ligase RNF5 (also known as RMA1) to promote autophagy protein ATG4B expression. Moreover, PTGDR2 knockdown blocked the activation of autophagy by PGD2 and the level of ATG4B ubiquitination in GCSCs.
In summary, it was elucidated that the PGD2/PTGDR2 signaling cascade affects GCSCs stemness by regulating autophagy, suggesting that the PGD2/PTGDR2 signaling pathway could serve as a novel target for cancer therapy.
前列腺素D2（PGD2）可抑制不同恶性肿瘤的发展；然而，其抑制肿瘤发展的潜在机制尚不清楚。本研究旨在阐明PGD2如何抑制胃癌干细胞（GCSCs）的干性、自噬及其潜在分子机制，为胃癌治疗提供理论依据。
在本研究中，通过无血清培养富集GCSCs。此外，采用蛋白质免疫印迹法、免疫荧光分析和透射电子显微镜检测PGD2和PGD2受体（PTGDR2）对自噬的影响。此外，采用免疫沉淀等方法评估ATG4B的泛素化水平。
结果表明，PGD2诱导GCSCs中LC3I/LC3II转化以激活自噬，而PGD2促进PTGDR2的表达，从而进一步激活自噬。此外，PTGDR2与ATG4B竞争与E3连接酶RNF5（也称为RMA1）结合，以促进自噬蛋白ATG4B的表达。此外，PTGDR2基因敲低可阻断PGD2对GCSCs自噬的激活以及ATG4B的泛素化水平。
综上所述，阐明了PGD2/PTGDR2信号级联通过调节自噬影响GCSCs的干性，提示PGD2/PTGDR2信号通路可作为癌症治疗的新靶点。
