肿瘤胞外PDI在玻连蛋白介导的乳腺癌细胞转移过程中的作用

Breast cancer is the most common malignancy in females, accounting for approximately 15% of all newly diagnosed female cancer cases in China each year. Vitronectin, an important plasma component and extracellular matrix protein, has been shown to be important for breast cancer metastasis. The source of vitronectin in breast tumor tissues is derived from infiltrating blood cells (such as platelets) and plasma by vessel leakage, rather than from de novo protein synthesis by tumor cells. It is noteworthy that native plasma vitronectin is unable to bind its ligand integrin, and it remains elusive how this binding occurs during tumor metastasis. Our recent published work has identified vitronectin as a substrate of extracellular protein disulfide isomerase (PDI). Based on this finding and our preliminary results, we proposed that reduction of vitronectin by extracellular PDI of tumor cells enables the binding of vitronectin to integrin. This project will utilize approaches of protein chemistry and tumor biology, in combination with a series of in vitro and in vivo methods. The aim is to dissect the functional activity of PDI on the surface of breast cancer cells, and its role in vitronectin induced breast cancer metastasis. This project has the potential to reveal an unrecognized role of extracellular PDI on tumor cells and extend our knowledge about the role of extracellular PDI in the field of breast cancer metastasis. Completion of this project will provide guidance and theoretical basis for the development of PDI inhibitors as an anti-cancer therapy.

乳腺癌是我国女性中最常见的恶性肿瘤，约占女性新发癌症病例的15%。玻连蛋白（vitronectin）作为一种重要的血浆和胞外基质蛋白，通过结合整合素诱导乳腺癌细胞的转移，但是血浆中天然的玻连蛋白并不能结合整合素，该结合过程在肿瘤转移时是如何实现的还未有报道。申请人前期发表的研究工作鉴定出玻连蛋白是胞外蛋白质二硫键异构酶（PDI）的底物，本项目基于该发现和申请人回国后的初步研究结果，推理认为肿瘤胞外PDI对玻连蛋白的还原修饰作用能增强其结合整合素的能力。该项目拟结合蛋白质化学和肿瘤生物学相关的研究方法，逐步通过一系列体外和体内的实验手段，检测PDI在乳腺癌细胞表面的活性以及该活性在玻连蛋白通过整合素诱导肿瘤细胞迁移这一过程中的关键作用。本项目的成功意义重大，将胞外PDI蛋白的功能拓展到乳腺癌转移领域，将开拓PDI在肿瘤中崭新的作用通路，为PDI抑制剂在乳腺癌治疗中的潜在应用提供理论基础。

乳腺癌是我国女性中最常见的恶性肿瘤，约占女性新发癌症病例的15%。玻连蛋白（VTN）作为一种重要的血浆和胞外基质蛋白，通过结合整合素诱导乳腺癌细胞的转移，但是血浆玻连蛋白结合肿瘤细胞表面受体的分子机制未知。本项目通过一系列蛋白质化学和肿瘤生物学相关的研究方法，发现乳腺癌细胞表面的蛋白质二硫键异构酶（PDI）能够催化玻连蛋白VTN上的二硫键重排，增强VTN促进肿瘤转移的作用。荧光免疫染色和流式细胞术证实乳腺癌细胞表面表达PDI蛋白，其分泌量随细胞活化而增加，且胞外PDI能显著增加血浆VTN在肿瘤细胞表面的结合。PDI抑制剂能特异性减少VTN介导的乳腺癌细胞增殖和迁移。进一步的分子机制研究发现，PDI通过增强VTN介导的AKT/mTOR/4EBP1信号通路而促进肿瘤细胞的转移。通过分析乳腺癌患者的临床样本发现，血浆PDI含量和乳腺癌的发生和转移密切相关。本项目具有重要的科学和临床意义，揭示了胞外PDI在乳腺癌转移过程中的关键作用，开拓了PDI在肿瘤中崭新的作用通路，为PDI抑制剂在乳腺癌治疗中的潜在应用提供了理论基础。