ETV4通过调控中性粒细胞胞外陷阱形成促进膀胱癌淋巴转移的功能与机制研究

中性粒细胞胞外陷阱（Neutrophil extracellular traps，NETs）与乳腺癌及结肠癌的远端转移密切相关。然而，NETs是否参与膀胱癌淋巴转移进程尚未可知。我们研究发现，转录因子ETV4在膀胱癌中高表达，与膀胱癌病人生存预后紧密相关。通过体外敲低或过表达实验及体内足垫淋巴转移模型分析发现，ETV4促进膀胱癌淋巴转移。机制研究发现，ETV4 140位丝氨酸磷酸化对其核转位功能至关重要，ETV4被磷酸化入核后，在LAP2的协助下转运至染色质，结合到CXCL2/8的启动子上，促进其转录与表达。敲低ETV4抑制膀胱癌细胞对中性粒细胞浸润及NETs形成。通过以上研究发现，我们推测，ETV4通过促进CXCL2/8表达调控中性粒细胞浸润及NETs形成影响膀胱癌淋巴转移。

Neutrophil extracellular traps(NETs) promotes tumor cells in metastatic colonization . However, litte is known whether lymph node (LN) metastasis in bladder cancer is associated with NETs. Here, we show that transcription factor ETV4 is upregulated in bladder cancer and associated with LN metastasis and prognosis. Through gain and loss of function approaches, we find that ETV4 promotes bladder cancer lymphatic metastasis. Mechanistically, phosphorylation of ETV4 at serine 140 promotes its nuclear translocation; after nuclear translocation, ETV4 is translocated to chromatin by LAP2, which epigenetically activates CXCL2/8 expression. Furthermore, knock-down of ETV4 reduced the recruitment of neutrophils to the bladder cancer cell and NETs formation.Upon those findings, we suppose that ETV4 mediated neutrophils recruitment and NETs formation by activating CXCL2/8 expression are associated with bladder cancer LN metastasis.