Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Jining, Shandong, People's Republic of China.
Stem Cells. 2018 Jul;36(7):990-1003. doi: 10.1002/stem.2821. Epub 2018 Apr 4.
The antitumor effect of prostaglandin D2 (PGD2) on gastric cancer (GC) has been known for decades. However, the mechanism of PGD2's control of GC growth is unclear. Cancer stem cells (CSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. Herein, we discovered that signaling between PGD2 and its receptor (PTGDR2) has the ability to restrict the self-renewal of GC cells in vitro and suppress tumor growth and metastasis in vivo. To obtain these findings, we first determined that PGD2 synthase (L-PTGDS) and PTGDR2 expression were lower in GC tissues than adjacent tissues and was associated with the patients' prognosis. Moreover, the expression of L-PTGDS and PTGDR2 was negatively correlated with the GC-CSC markers Sall4 and Lgr5 in GC tissues. Second, L-PTGDS and PTGDR2 expression were knocked down in CSC-like cells, resulting in enhanced expression of CSC markers and self-renewal ability. Direct PGD2 stimulation and L-PTGDS overexpression produced the opposite effect. Thirdly, PGD2 inhibited tumor growth and incidence rate in a subcutaneous tumor model and suppressed liver and mesenteric metastasis in a peritoneal metastasis model. Interfering with the expression of PTGDR2 reversed these effects in vivo. Last, a mechanistic study found that PGD2 inhibited STAT3 phosphorylation and nuclear expression. Further experiments revealed that the inhibitory effect of PGD2 on the expression of CSC markers disappeared after mutations were introduced into STAT3 phosphorylation (Thr705) site. In short, this study reveals a novel function of PGD2/PTGDR2 signaling on CSC regulation and provides a new way to control the development of GC. Stem Cells 2018;36:990-1003.
前列腺素 D2（PGD2）对胃癌（GC）的抗肿瘤作用已被人们了解了数十年。然而，PGD2 控制 GC 生长的机制尚不清楚。肿瘤干细胞（CSC）与肿瘤新生血管形成、侵袭和治疗耐药性有关。在此，我们发现 PGD2 与其受体（PTGDR2）之间的信号具有限制 GC 细胞在体外自我更新以及在体内抑制肿瘤生长和转移的能力。为了获得这些发现，我们首先确定 PGD2 合酶（L-PTGDS）和 PTGDR2 的表达在 GC 组织中低于相邻组织，并且与患者的预后相关。此外，GC 组织中 L-PTGDS 和 PTGDR2 的表达与 GC-CSC 标志物 Sall4 和 Lgr5 呈负相关。其次，在类 CSC 细胞中敲低 L-PTGDS 和 PTGDR2 的表达，导致 CSC 标志物的表达增强和自我更新能力增强。PGD2 的直接刺激和 L-PTGDS 的过表达产生相反的效果。第三，PGD2 在皮下肿瘤模型中抑制肿瘤生长和发生率，并抑制腹膜转移模型中的肝和肠系膜转移。体内干扰 PTGDR2 的表达会逆转这些作用。最后，一项机制研究发现 PGD2 抑制 STAT3 磷酸化和核表达。进一步的实验表明，PGD2 对 CSC 标志物表达的抑制作用在 STAT3 磷酸化（Thr705）位点发生突变后消失。总之，这项研究揭示了 PGD2/PTGDR2 信号对 CSC 调控的新功能，并为控制 GC 的发展提供了一种新方法。干细胞 2018;36:990-1003.
