EBP50通过调控FSGS表达对舌鳞癌侵袭和转移影响的机制研究

Tongue squamous cell carcinoma is the second most common type of head and neck cancer worldwide. Tongue squamous cell carcinoma experiences lymph node metastasis frequently, and the metastasis status directly affects the prognosis and survival rate. The invasive and metastatic potential of cancer cells are closely related to the assembly of microfilament system. FSGS is a F-actin cross-linking protein which plays a critical role in regulating of the microfilament system. Lines of evidence demonstrated that the abnormal expression of FSGS was essential to tumor invasion and metastasis. However, the molecular mechanism of FSGS expression regulation in tongue squamous cell carcinoma was illusive. Our preliminary studies suggested that EBP50 can interact with FSGS. Overexpression of EBP50 inhibited cell migration and decreased FSGS expression in tongue squamous carcinoma cells SCC-6. In this project, we will clarify the interaction of EBP50 and FSGS in tongue squamous cell carcinoma, and further study the effect of this interaction on microfilament cytoskeleton system and metastasis in tongue squamous cell carcinoma. The results of this study will help to elucidate the molecular mechanism of FSGS expression regulation and effects on tongue squamous cell carcinoma metastasis by EBP50. Moreover, it will reveal a novel mechanism of the microfilament cytoskeleton assembly, and provide a theoretical basis for finding new drug targets against tongue squamous cell carcinoma invasion and metastasis.

舌鳞癌是第二高发的头颈部肿瘤，极易发生淋巴结转移，其转移状况直接影响患者的预后和存活率。肿瘤的转移与细胞骨架，尤其是微丝骨架的动态变化密切相关。微丝结合蛋白FSGS表达失调是肿瘤细胞发生侵袭和转移的重要原因，而目前有关FSGS在舌鳞癌中表达调控的分子机制尚无报道。我们的初步研究表明，肿瘤相关蛋白EBP50与FSGS相互作用，在SCC-6舌鳞癌细胞中过表达EBP50抑制了细胞的迁移并下调了FSGS的表达。在此基础上，本课题拟采用多种方法确认EBP50与FSGS在舌鳞癌细胞中的相互作用，研究该相互作用调节FSGS表达的机制，探索该相互作用对舌鳞癌细胞微丝骨架组装和转移的影响。本课题的研究不仅有助于阐明舌鳞癌细胞中EBP50调节FSGS表达及影响舌鳞癌细胞转移的分子机制，揭示了一种调节细胞微丝骨架组装的新模式，而且为以EBP50或其与FSGS相互作用为靶标的抗舌鳞癌转移药物的研发提供了理论依据。

舌鳞癌是第二高发的头颈部肿瘤，极易发生淋巴结转移，其转移状况直接影响患者的预后和存活率。组织芯片研究发现，与正常舌上皮组织相比，舌鳞状细胞癌组织中肿瘤相关蛋白EBP50显著低表达，而FSGS高表达。进一步研究发现，EBP50可以通过其PDZ1结构域直接与FSGS羧基末端的PDZ结合基序相互作用，从而降低FSGS的蛋白表达水平，同时不影响其mRNA的表达量。此外，我们发现EBP50的表达抑制了舌鳞癌细胞体外迁移和侵袭的能力，同时小鼠体内转移模型显示EBP50的表达抑制了舌鳞癌细胞在裸鼠体内的转移能力。研究发现，EBP50与FSGS的相互作用导致舌鳞癌细胞中F-actin的表达量明显降低，细胞中肌动蛋白骨架的组装受到抑制，最终抑制了舌鳞癌细胞迁移和侵袭的能力。本研究不仅阐明了舌鳞癌细胞中EBP50调节FSGS表达及影响舌鳞癌细胞转移的分子机制，而且为以EBP50或其与FSGS相互作用为靶标的抗舌鳞癌转移药物的研发提供了理论依据。