CCL22/CCR4介导的淋巴窦内皮细胞定向诱导宫颈癌淋巴结转移的作用及其机制研究

淋巴结转移是宫颈癌患者致死的主要原因。研究发现转移淋巴结内的淋巴窦内皮细胞可分泌趋化因子靶向癌症细胞定向诱导肿瘤发生淋巴结转移。然而，转移淋巴结微环境中趋化因子促宫颈癌细胞定向转移的作用尚未阐明。我们预实验发现，转移淋巴结中淋巴窦内皮细胞可分泌趋化因子CCL22。同时，CCL22的受体CCR4在转移阳性宫颈癌临床标本中高表达。由此，我们推测：淋巴窦内皮细胞分泌趋化因子CCL22靶向诱导CCR4阳性细胞发生宫颈癌定向淋巴结转移。因此，本项目拟进一步利用体内外模型验证CCL22/CCR4促宫颈癌淋巴结定向转移的作用；阐明CCR4受LncRNA-RMRP-miRNA-25 ceRNA网络调控后表达上调，通过ERK/AKT/FAK通路促宫颈癌淋巴结转移的具体机制。本研究从转移微环境中趋化因子靶向阳性受体癌细胞角度揭示宫颈癌淋巴结定向转移的新机制，为宫颈癌患者提供潜在的淋巴结转移预警分子。

Lymph node metastasis contributes largely to the mortality of cervical cancer patients. Researchers have discovered that lymphatic sinus endothelial cell can secrete chemokines to target cancer cells and induce them to metastasize into lymph nodes. However, the chemokines in metastatic niche of lymph node have not been well studied in cervical cancer metastasis. Our pre-experiments indicated that the lymphatic sinus endothelial cell could secrete C-C motif chemokine 22(CCL22). Meanwhile, its receptor, C-C chemokine receptor type 4(CCR4) was upregulated in metastasis positive cervical cancer patient samples. Therefore, we put forward our hypothesis: lymphatic sinus endothelial cell secretes CCL22 to induce CCR4 positive cervical cancer cell to metastasize into lymph nodes. Thus, the present project will further prove the effect of CCL22/CCR4 axis in cervical cancer lymph node metastasis and discover the detailed mechanism that LncRNA-RMRP-miRNA-25 ceRNA network regulates CCR4 expression, activating ERK/AKT/FAK pathway to promote cervical cancer lymph node metastasis. This study may shed a light to the detailed molecular mechanism behind cervical cancer lymph node metastasis, from the perspective that chemokines in the metastatic niche can target certain receptor positive population. If proven, the present research may provide potential biomarker for cervical cancer patients with lymph node metastasis.