PGD2/PTGDR2 Signaling Restricts the Self-Renewal and Tumorigenesis of Gastric Cancer
PGD2/PTGDR2 Signaling Restricts the Self-Renewal and Tumorigenesis of Gastric Cancer
复制标题
PGD2/PTGDR2 信号传导限制胃癌的自我更新和肿瘤发生
作者：
Zhang Bin;Bie Qingli;Wu Peipei;Zhang Jie;You Benshuai;Shi Hui;Qian Hui;Xu Wenrong
摘要前列腺素D2（PGD 2）对胃癌的抗肿瘤作用已被人们认识了几十年。然而，PGD 2控制GC生长的机制尚不清楚。癌症干细胞（CSC）与肿瘤新生血管形成、侵袭性和治疗抗性有关。在此，我们发现PGD 2和其受体（PTGDR 2）之间的信号传导具有在体外限制GC细胞的自我更新和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PGD 2合酶（L-PTGDS）和PTGDR 2在GC组织中的表达低于邻近组织，并且与患者的预后相关。胃癌组织中L-PTGDS和PTGDR 2的表达与胃癌CSC标志物Sall 4和Lgr 5呈负相关。第二，L-PTGDS和PTGDR 2在CSC样细胞中的表达被敲低，导致CSC标志物的表达和自我更新能力增强。直接PGD 2刺激和L-PTGDS过表达产生相反的效果。第三，PGD 2在皮下肿瘤模型中抑制肿瘤生长和发病率，在腹膜转移模型中抑制肝和肠系膜转移。干扰PTGDR 2的表达在体内逆转了这些作用。最后，一个机制研究发现，PGD 2抑制STAT 3磷酸化和核表达。进一步的实验表明，在STAT 3磷酸化位点（Thr 705）引入突变后，PGD 2对CSC标志物表达的抑制作用消失。总之，本研究揭示了PGD 2/PTGDR 2信号通路在CSC调控中的新功能，为控制GC的发生发展提供了新的思路。
AbstractThe 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.