卵巢癌和腹腔巨噬细胞之间14-3-3 zeta蛋白介导的胞外信号互动及其促转移作用机制的研究

One of the critical tasks of ovarian cancer research is to clearly elucidate the interactions between the cancer cells and the local microenvironment as well as their clinical consequences. In our previous study, we found that the cancer cells could release a large amount of 14-3-3 zeta molecules during the early stage of their malignant transformation and metastasis, which leads to a poor prognosis of the patients. Our works were noted by international peers, and the afterwards in-depth investigation revealed that the secreted 14-3-3 zeta protein is capable of modulating the immune microenvironment surrounding the cancer cells and promoting the involved tumor-associated macrophages to differentiate into an unfavorable phenotype M2, which favors the progression of cancer tissues. Our research proposal is to analyze the interactions between ovarian cancer cells and peritoneal macrophages based on the extracellular signal transmission activity of 14-3-3 zeta protein. We expect to find out the membrane receptor- and/or exosome-based 14-3-3 zeta signaling pathways, by which the progression of ovarian cancer could be accelerated. Further, we plan to construct a liposome-monoclonal antibody complex system to block the extracellular signaling pathways of 14-3-3 zeta, whereby the disadvantage local microenvironment condition of ovarian cancer patients could be reverted and their long-term prognoses could be improved. Our research proposal is original, which has never been brought forward by any other fellow researchers. It can direct our research efforts towards unveiling the role of 14-3-3 zeta as a dual messenger to transmit both the intra- and extracellular biological signals within/to the target cells and unveiling the roles that exosomes have ever played during this process. It also provides a novel therapeutic strategy to block disadvantage exosome-meidated extracellular signaling pathways in the cancer tissue.

卵巢癌研究关键之一在于阐述清楚癌细胞和局部微环境之间的互动关系及其临床后果。在前期研究中，我们发现卵巢癌恶性转化和早期转移过程中会释放出大量14-3-3 zeta蛋白分子，使患者预后变差。我们工作得到国际同行关注，其后深入研究发现分泌型14-3-3 zeta具有调控免疫微环境，使肿瘤相关巨噬细胞（TAM）向不利于预后M2表型分化的能力。本研究拟分析14-3-3 zeta胞外信号传递机制基础上的癌细胞-腹腔巨噬细胞相互作用关系，利用免疫共沉淀-质谱技术找到维持这种互动关系的膜受体和外泌体信号通路，阐明其对于卵巢癌发生发展的促进作用。并且，通过构建脂质体-特异性单抗复合物阻断这种信号通路，逆转不良微环境，改善预后。我们的研究计划具有一定的首创性，阐述清楚了14-3-3 zeta这种传统胞内信号元件如何作为双功能信使发挥胞外信号作用，外泌体在其中所起的作用，以及阻断这种作用的新型靶向干预方法。

本研究针对卵巢癌患者中癌细胞所释放14-3-3zeta蛋白与腹腔巨噬细胞之间的分子信号互动关系、作用机制及其临床意义进行了深入研究。研究证实，腹水中14-3-3zeta蛋白主要以外泌体形式存在，能够诱导腹腔巨噬细胞向M2方向分化，能够促进癌细胞转移。免疫共沉淀研究证实，14-3-3zeta蛋白能够与巨噬细胞膜上的MHC I类分子（HLA-A、HLA-B、HLA-C）以及抗原处理分子（TAP2、ERAP1、PSMA3、PSMA4、PSMA6、PSMB4、 PSMD14）结合，阻断M1型巨噬细胞杀伤癌细胞/提呈肿瘤抗原的天然免疫功能，并促进其向M2型分化，从而导致腹水形成、癌细胞生长转移加速。构建脂质体-14-3-3 zeta 单抗复合物有助于消除14-3-3zeta蛋白的不利影响，削弱/减少腹腔巨噬细胞M2型分化能力和比例，延缓肿瘤生长速度，延长存活时间。

内容获取失败，请点击重试