去泛素化酶OTUD3基因缺失诱导食管鳞癌淋巴结转移的分子机制

淋巴结转移是食管鳞癌最主要的转移方式，直接影响治疗的效果及患者的生存预后。寻找淋巴结转移的关键调控分子对食管癌的早期诊断和治疗具有重要的意义。近期，通过基因表达谱芯片筛选，我们发现去泛素化酶OTUD3在淋巴结转移性样品中表达明显下调。免疫共沉淀及质谱分析表明OTUD3与多个重要蛋白相互作用。其中，OTUD3可抑制IκB-α蛋白泛素化降解。OTUD3表达下调激活NF-κB信号通路。进一步预实验结果显示：上调 OTUD3表达可通过抑制①细胞外基质降解、②淋巴管新生、③肿瘤跨内皮细胞迁移等功能，进而多层面调控淋巴结转移的发生。并且，我们发现OTUD3基因存在广泛缺失，与其表达下调和肿瘤淋巴结转移显著相关。这些结果提示OTUD3基因缺失在食管鳞癌淋巴结转移中发挥重要作用。本研究将承前启后，深层次解析OTUD3基因缺失诱导淋巴结的分子机制，并与临床相结合，为食管鳞癌早期诊断及治疗提供新的理论依据。

Lymph node metastasis is the most common manner of metastasis in esophageal cancer, and is closely correlated with poor prognosis. Thus idenifying key molecular factor in lymphatic metastasis process would be of great value for early diagnosis and therapy. Recently, using the microarray screening, we found that the deubiquitinase OTUD3 is roubustly downregulated in the esophageal cancer tissues with lymph node metastasis. Furthermore, the immunoprecipitation assay revealed that OTUD3 interacts with multiple proteins including IκB-α. We then found that OTUD3 deubiquitinated the K48-linked ubiqutin chain of IκB-α, leading to its stability. As expected, high expression of OTUD3 inhibits NF-κB signaling. Moreover, we demonstrate that overexpression of OTUD3 supresses the capabilities of esophageal cancer cells to induce matrix degradation, lymphangiogenesis and transendothelial migration. Importantly, OTUD3 inhibits lymph node metastasis and distant metastasis in vivo. Finally, we identify that OTUD3 locus is lost in a large portion of esophageal cancer patients. Thus, our recent results suggest an important role of OTUD3 in lymph node metastasis. In the current project, we will combine in vivo and in vitro experimental systems with data from clinical samples, in order to investigate the multi-dimensional mechanisms of OTUD3 loss-induced esophageal cancer lymphatic metastasis. Our work may help identify novel diagnostic markers and therapeutic targets for esophageal cancer.