ERK3介导TNF-α调控头颈鳞癌淋巴管生成的作用及机制

项目名称： ERK3介导TNF-α调控头颈鳞癌淋巴管生成的作用及机制

项目编号： No.81502361

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张才云

作者单位： 中国人民解放军第二军医大学

项目金额： 18万元

中文摘要： 淋巴管生成是淋巴结转移的重要前提，而淋巴结转移大大影响头颈鳞癌的治疗效果，但淋巴管生成的机制尚不甚清楚。我们先前报道及预实验发现TNF-α与头颈鳞癌淋巴结转移密切相关，体外可以诱导淋巴管的生成，我们进一步预实验明确了ERK3介导TNF-α调控头颈鳞癌淋巴管生成的作用，结合文献在血管和淋巴管生成中ERK3信号通路及其家族成员与VEGF-C／VEGFR3信号通路的密切关系，我们推测ERK3介导TNF-α调控头颈鳞癌淋巴管生成通过VEGF-C／VEGFR3信号通路来实现。本课题通过离体、在体及队列研究，确认ERK3介导TNF-α对头颈鳞癌淋巴管生成的作用，明确ERK3介导TNF-α通过VEGF-C／VEGFR3信号通路对淋巴管生成的作用，从而阐明ERK3及其介导的TNF-α调控头颈鳞癌淋巴管生成的作用及分子机制。阐述了头颈鳞癌淋巴管生成的具体机制，有望筛选出对头颈鳞癌淋巴结转移有预测作用的靶标。

中文关键词： 头颈部肿瘤；淋巴管生成；淋巴结转移；ERK3；TNF-α

英文摘要： Lymph node metastasis is an important risk factor for the poor prognosis of patients with squasmous cell carcinoma of the head and neck (SCCHN), and its mechanism has not been fully clarified. The VEGF-C／VEGFR3 pathway plays a critical role in the lymph node metastasis of the majority cancer types, however, it was found that there was no association between VEGF-C／VEGFR3 expression and lymphatic metastasis of SCCHN, indicating that other pathways might be involved in this process. TNF-α, an important cytokine, plays a critical role in the initiation and regulation of immune and inflammatory responses. It has been shown that TNF-α could induce lymphangiogenesis under physical and pathological conditions, suggesting that it may play a pivotal role in the lymphatic metastasis of cancer. In our previous study, we found that TNF-α was associated with lymphatic metastasis of SCCHN, but the mechanism on TNF-α and lymphatic metastasis of SCCHN has not been fully clarified. ERK3, another member of MAPK subfamily, has been reported to play an important role in angiogenesis, a process similar to lymphangiogenesis, indicating that it may also play a vital role in TNF-α induced lymphangiogenesis. Thus, we conducted a pilot study and found that the expression of ERK3 was significantly increased in SCCHN tumor tissue, and its expression was associated with lymphangiogenesis and lymphatic metastasis of SCCHN. Furthermore, we also found that TNF-α could regulate the expression of ERK3 in human lymphatic endothelial cells. Thus, we hypothesized that TNF-α stimulates the lymphangiogenesis and lymphatic metastasis of SCCHN via the ERK3 pathway. To test the hypothesis, we will conduct a series of in vitro, in vivo and cohort studies to explore the roles of ERK3 in TNF-α-induced lymphangiogenesis and lymphatic metastasis of SCCHN, as well as the molecular mechanism underlying the observed findings. Therefore, this study will provide important theoretic basis for the lymphangiogenesis and lymphatic metastasis of SCCHN.

英文关键词： head and neck cancer;lymphangiogenesis;lymphatic metastasis;ERK3;TNF-α