ERp29对VEGF-C介导的胃癌微淋巴管形成的影响及其机制

ERp29 was closely associated with lymph metastasis of gastric cancer, but the mechanism involved is far from been fully elucidated. In our previous study, we found that ERp29 interacted with PPM1B, the important regulatory factor of the signaling pathways of NF-κB and MAPKs/AP-1. It had been well documented that NF-κB and MAPKs/AP-1 signaling pathways influent VEGF-C mediated lymphangiogenesis. Therefore, in this study, we will perform the following research to clarify the impacts of ERp29 on lymphatic metastasis of gastric cancer, the study includes: 1. Determining the binding domains of both ERp29 and PPM1B; 2. Investigating the VEGF-C production of gastric cancer cells regulated by ERp29-PPM1B interaction; 3. Elucidating the effects of ERp29-PPM1B interaction on NF-κB and MAPKs/AP-1 signaling, which contributed to VEGF-C production and the lymphangiogenesis of gastric cancer. Our present study will further reveal the mechanism of lymphatic metastasis of gastric cancer, and provide a new insight for the theoretical research of lymphatic metastasis and anti-cancer targeted drug design.

ERp29与胃癌的淋巴转移关系密切,但其机制尚未阐明。本课题组前期研究发现ERp29与PPM1B存在相互作用。PPM1B是NF-κB及MAPKs/AP-1信号通路的重要调控因子, 而该通路可调控与淋巴管形成密切相关的VEGF-C的产生。为此，本课题拟进行如下研究以阐明ERp29对VEGF-C介导的胃癌微淋巴管形成的影响及其机制：1) ERp29和PPM1B相互作用的各自的功能区段；2) ERp29通过与PPM1B的相互作用调控胃癌细胞VEGF-C的生成；3) ERp29和PPM1B的相互作用调控PPM1B介导的信号通路，进而影响VEGF-C生成并最终影响胃癌微淋巴管的形成。研究结果将进一步揭示胃癌淋巴转移的机制，为抗胃癌淋巴转移理论研究和靶向药物设计提供新思路。

胃癌有易复发和转移的特点，其中淋巴转移是胃癌转移的重要方式，寻找淋巴转移特异性标志物并阐明其在胃癌转移发生发展中的分子机制具有重要的理论和临床意义。申请者前期研究发现ERp29在胃腺癌组织表达显著降低；ERp29表达低的胃癌组织，VEGF-C的表达显著增强；ERp29与PPM1B存在相互作用。但目前尚不知ERp29是否通过与PPM1B相互作用参与NF-κB- VEGF-C信号通路，进而调控胃癌淋巴转移和微淋巴管形成。本项目主要研究ERp29是否通过与PPM1B相互作用调控NF-κB- VEGF-C信号通路，进而调控胃癌淋巴转移和微淋巴管形成，以及涉及的具体机制，从而为胃癌淋巴转移的研究与治疗提供理论依据。.本项目通过组织学证实ERp29高表达的胃癌组织中淋巴管数目减少，细胞学实验证实细胞敲低ERp29水平促进了淋巴管成环数量，动物学实验证实过表达ERp29可抑制皮下成瘤淋巴转移能力。胃癌细胞学研究发现，ERp29的敲低，促进VEGF-C的表达。证实ERp29与PPM1B相互作用，并通过NF-kB通路抑制VEGF-C的表达，从而抑制胃癌微淋巴管的生成。.综上所述：本项目发现ERp29通过与PPM1B相互作用调控NF-κB—VEGF-C信号通路，进而调控胃癌淋巴形成和转移及其具体机制，若促进ERp29的表达可以减少肿瘤的淋巴转移，为后续临床应用打下坚实基础。