CCL25/CCR9生物轴促进非小细胞肺癌淋巴结转移的机制研究

Lung cancer is one of the most common malignant cancers in the world. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and lymph node metastasis is the main causes of NSCLC patient’s treatment failure. Therefore, how to prevent NSCLC cells invasion and lymph node metastasis is an important issue in the present control of NSCLC cancer progress. In previous studies, we have confirmed that CC chemokine receptor-9 (CCR9), interact with its natural ligand CCL25, promotes NSCLC cells invasion and migration, and its expression is associated with lymph node metastasis of NSCLC patients. To investigate the potential role and mechanism activated by the CCL25/CCR9 biological axis in the lymph node metastasis process of NSCLC, the project will take advantage of CCR9 gene silencing stably transfected cell lines which was successfully constructed in the previous study, establish CCR9 gene silencing NSCLC cells and nude mice lymph node metastasis model, explore the expression changes and internal relations of signaling pathways, tumor metastasis markers, lymphatic markers and lymphangiogenesis factors in the tumor microenvironment and nude mice models when CCL25/CCR9 biological axis was blocked，clarify the role and regulation mechanism of CCL25/CCR9 biological axis in the NSCLC lymph node metastasis process and provide a theoretical basis for the future CCL25/CCR9 biological axis as NSCLC lymph node metastasis therapeutic targets.

肺癌是世界上最常见的恶性肿瘤之一，非小细胞肺癌约占肺癌的85%，淋巴结转移是非小细胞肺癌治疗失败的主要原因。因此，如何阻止非小细胞肺癌向淋巴结及远处转移是目前临床治疗中亟待解决的关键问题。我们前期研究发现，趋化因子受体CCR9与其单一配体CCL25相互作用,促进非小细胞肺癌细胞侵袭和迁移，且与非小细胞肺癌患者淋巴结转移密切相关。为了深入探讨CCL25/CCR9生物轴在非小细胞肺癌淋巴结转移过程中的潜在作用和机制，本项目将利用前期研究中成功构建的沉默CCR9基因的稳转细胞系,建立非小细胞肺癌淋巴结转移的细胞和裸鼠模型，探讨阻断CCL25/CCR9生物轴后，相关信号通路、肿瘤迁移标记物、淋巴管标记物及淋巴管生成因子等在肿瘤微环境和裸鼠模型中的表达变化及其内在联系，阐明CCL25/CCR9生物轴在非小细胞肺癌淋巴结转移过程中的作用及调控机制，为今后CCL25/CCR9生物轴作为非小细胞肺癌淋巴

肺癌是世界上发病率和死亡率最高的恶性肿瘤，淋巴结转移是影响患者治疗决策和远期预后的主要因素。本项目研究发现，CCL25在非小细胞肺癌（NSCLC）患者外周血清中表达升高，CCR9在癌组织中阳性表达，它们与患者淋巴结转移、TNM分期密切相关，并表达水平与肿瘤转移因子VEGF、MMP2及MMP9正相关。血清中CCL25表达水平可应用于NSCLC患者的术前早期诊断、淋巴结转移发生风险评估等。CCL25/CCR9相互作用增强NSCLC细胞的迁移和侵袭能力，CCR9过表达促进裸鼠体内成瘤能力。CCL25/CCR9生物轴相互作用可能通过激活PI3K/AKT信号转导通路关键蛋白及下游转移相关因子（VEGF-C/D、MMP2/9等）的表达，诱导NSCLC细胞侵袭与迁移，从而导致淋巴结转移。在循环肿瘤细胞（CTC）检测阳性的NSCLC患者中，CTC上CCR9表达水平显著升高，肺鳞癌患者混合型CTC中CCR9阳性率高于肺腺癌患者，混合型CTC的CCR9阳性率与NSCLC远处转移密切相关。CTC上CCR9表达水平有望用作评估NSCLC肿瘤远处转移风险的生物标志物。基于生物信息学分析，CCL25与驱动蛋白超家族成员KIF18A、KIF18B表达密切相关，后两者是新发现的致癌基因。KIF18A、KIF18B在肺腺癌中异常高表达，促进肿瘤增殖、逃避凋亡，并与患者淋巴结转移、TNM分期相关，影响患者OS和（或）RFS，是预测不良预后的独立因素。CCR9/CCCL25生物轴在NSCLC发生、演进和淋巴结转移中发挥重要作用，是一个治疗NSCLC的潜在治疗靶点，深入研究CCL25/CCR9生物轴有助于理解肺癌的淋巴结转移机制。