The novel ZEB1-upregulated protein PRTG induced by Helicobacter pylori infection promotes gastric carcinogenesis through the cGMP/PKG signaling pathway.
The novel ZEB1-upregulated protein PRTG induced by Helicobacter pylori infection promotes gastric carcinogenesis through the cGMP/PKG signaling pathway.
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幽门螺杆菌感染诱导的新型ZEB1上调蛋白PRTG通过cGMP/PKG信号通路促进胃癌发生。
DOI：
10.1038/s41419-021-03440-1
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发表时间：
2021-02-04
影响因子：
9
通讯作者：
Liu G
中科院分区：
文献类型：
--
作者：
Xiang T;Yuan C;Guo X;Wang H;Cai Q;Xiang Y;Luo W;Liu G
幽门螺杆菌（H. pylori）被列为人类胃癌的I类致癌物;然而，对潜在的机制知之甚少。在这项研究中，我们发现Protogenin（PRTG）在胃癌组织和H。通过分析TCGA和GEO数据库中的失调基因，对幽门螺杆菌感染的组织进行研究。重要的是，上调的PRTG预测胃癌患者的不良预后，综合分析显示，PRTG在胃癌中作为一种致癌蛋白，是H.在体外细胞和体内荷瘤小鼠模型中幽门介导的致瘤活性。机械，H。在生物信息学和细胞研究中，pylori感染通过促进转录因子ZEB 1稳定和募集到PRTG启动子来增强PRTG表达，然后激活亚后续的cGMP/PKG信号通路。细胞研究进一步证实PRTG依赖于激活cGMP/PKG轴促进胃癌细胞的增殖、转移和耐药。PKG抑制剂KT 5823与顺铂和紫杉醇在体外细胞和体内荷瘤小鼠模型中对胃癌细胞具有协同抗肿瘤作用。综上所述，我们的研究结果表明，H。pylori感染依赖于ZEB 1诱导PRTG表达上调，并通过激活cGMP/PKG信号通路导致胃癌的发生发展。因此，阻断PRTG/cGMP/PKG轴为胃癌的治疗提供了一个有希望的新策略。
Helicobacter pylori (H. pylori) is listed as a class I carcinogen in human gastric cancer; however, the underlying mechanisms are poorly understood. In this study, we identified Protogenin (PRTG) was upregulated in both gastric cancer tissues and H. pylori-infected tissues by analyzing dysregulated genes in TCGA and GEO databases. Importantly, upregulated PRTG predicted poor prognosis of gastric cancer patients and integrative analysis revealed that PRTG served as an oncogenic protein in gastric cancer and was required for H. pylori-mediated tumorigenic activities in in vitro cellular and in vivo tumor-bearing mouse models. Mechanistically, H. pylori infection enhanced PRTG expression by promoting transcriptional factor ZEB1 stabilization and recruitment to the PRTG promoter, and which then activated the sub-following cGMP/PKG signaling pathway in bioinformatic and cellular studies. Cellular studies further confirmed that PRTG depended on activating cGMP/PKG axis to promote proliferation, metastasis, and chemoresistance of gastric cancer cells. The PKG inhibitor KT5823 played synergistic anti-tumor effects with cisplatin and paclitaxel to gastric cancer cells in in vitro cellular and in vivo tumor-bearing mouse models. Taken together, our findings suggested that H. pylori infection depends on ZEB1 to induce PRTG upregulation, and which leading to the development and progression of gastric cancer through activating cGMP/PKG signaling pathway. Blocking PRTG/cGMP/PKG axis, therefore, presents a promising novel therapeutic strategy for gastric cancer.
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