Arf6介导CCL18促进乳腺癌转移的机制研究

Epithelial mesenchymal transition of tumor cell is one of the most important reasion of tumor metastasis. It is remain unknow that the critical point or mechanism of epithelial mesenchymal transition promoted by inflammatory factors. Previously we reported that CCL18 induced epithelial mesenchymal transition 【Caner Cell，2014】. Recently we found that: ①CCL18 activated Arf6 pathway (including GEP100-Arf6-AMAP1) via its receptor on cell membrance PITPNM3. ②Arf6 mediated CCL18-induced aggregation of integrinβ1, as well as adhesion. ③Arf6 promoted epithelial mesenchymal tranition of MCF-7 cell line on the stimulation of CCL18. ④ It appears that positive correlation between expression of CCL18 and AMAP1, an effector of Arf6, which was predictive of poor prognoses in breast cancer patients. In this project, we will investigate the molecular mechanism of Arf6 in promoting CCL18-induced epithelial mesenchymal tranition, as well as metastasis in breast cancer. Thus provide the experiment basis of the pharmaceutical targeting of Arf6 as a promising novel treatment for breast cancer.

目前已知肿瘤细胞上皮间质转化是肿瘤转移的主要原因；然而炎症因子促进肿瘤细胞上皮间质转化的关键节点和调控机制目前仍不清楚。前期研究中我们报道炎症因子CCL18促进乳腺癌细胞上皮间质转化【Caner Cell，2014】；近期预实验结果显示①CCL18通过PITPNM3受体激活Arf6通路蛋白（GEP100-Arf6-AMAP1）；②Arf6介导CCL18促进乳腺癌细胞整合素β1聚集而促进细胞粘附；③Arf6介导CCL18促进乳腺癌细胞上皮间质转化的现象；④Arf6效应器AMAP1与CCL18表达呈正相关趋势，与乳腺癌患者预后差相关。本项目将在前期研究基础上，采用体内体外系统，并结合临床标本，深入探讨Arf6调控CCL18诱导乳腺癌细胞上皮间质转化、促进乳腺癌转移的机制及生物学功能，为治疗乳腺癌提供新的分子靶点。

AMAP1是一种GTPase激活蛋白，可以调节细胞骨架结构的局部粘连、质膜折皱和促进肿瘤细胞分化。但是AMAP1在乳腺癌中的活化和功能仍不清楚。我们发现AMAP1在CCL18的作用下被磷酸化并转移到质膜上，与Pyk2形成稳定的复合物。此外，CCL18依赖的 AMAP1易位干扰AMAP1和IKK-β之间的相互作用，导致NF-κB激活。RNAi抑制AMAP1的表达能有效逆转CCL18诱导的乳腺癌细胞上皮间质转化以及粘附、迁移和侵袭。值得注意的是，在转移性乳腺癌中发现AMAP1过表达，并且对乳腺癌的不良预后具有很强的预测作用。鉴于AMAP1介导CCL18从而诱导NF-κB激活和促进乳腺癌转移，AMAP1可能是治疗乳腺癌转移的重要靶点。

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