FXR通过IL-6ST/Jak2/STAT3信号通路调控非小细胞肺癌转移的机制及治疗策略研究

Tumor metastasis is an important prognostic factor for non-small cell lung cancer (NSCLC), but the underlying molecular mechanisms remain to be elucidated. Our former studies showed that farnesoid X receptor (FXR) is increased in non-classical NSCLC tissues, which contributes to NSCLC tumor growth via transactivating cyclin D1 and modulating anti-tumor immunity. However, whether or not FXR affects NSCLC metastasis remains unexplored. Our preliminary experiments indicated that ①FXR promotes NSCLC metastasis; ②KEGG analysis revealed a significant correlation between FXR and metastasis-related STAT3 pathway; ③Mechanistic investigation showed that FXR directly binds to the IL-6ST promoter and activates its transcription. Therefore, we hypothesize that FXR could transactivate IL-6ST to facilitate IL-6ST/Jak2/STAT3 pathway activation, which finally promotes NSCLC metastasis. This project will be carried out, at multiple levels of clinical samples, cell experiments and animal models, to validate the functional role of IL-6ST/Jak2/STAT3 signals in FXR-induced NSCLC metastasis, explore the molecular mechanisms for FXR-activated IL-6ST/Jak2/STAT3 pathway, and evaluate the therapeutic efficacy of FXR inhibitor in treating NSCLC metastasis. This project will not only extend new mechanisms of NSCLC metastasis, but also provide new ideas for clinical diagnosis and therapy.

肿瘤转移是影响非小细胞肺癌（NSCLC）预后的重要因素，但分子机制需进一步阐明。我们既往研究发现法尼酯X受体FXR在“非经典”NSCLC组织中表达增多，通过调控cyclin D1转录和抗肿瘤免疫促进NSCLC肿瘤生长，然而FXR是否影响NSCLC转移仍未探究。预实验发现：①FXR可促进NSCLC肿瘤转移；②KEGG分析显示FXR与肿瘤转移相关STAT3通路存在显著关联；③机制研究显示FXR直接结合IL-6ST启动子并促进转录。故提出假说：FXR通过调控IL-6ST转录，激活IL-6ST/Jak2/STAT3通路，从而促进NSCLC转移。本课题将从临床样本、细胞实验、动物实验多层面展开，明确FXR通过IL-6ST/Jak2/STAT3通路促进NSCLC转移，探究FXR调控该信号通路的分子机制，观察FXR抑制剂对NSCLC转移的治疗效果。本课题将拓展NSCLC转移新机制，为临床诊治提供新思路。

肺癌是世界上发病率和死亡率最高的恶性肿瘤之一，约85%为非小细胞肺癌NSCLC。NSCLC预后较差，主要与肿瘤的复发和转移密切相关，然而调控NSCLC转移的分子机制目前仍不清楚。以PD-1/PD-L1抗体为代表的肿瘤免疫治疗正逐渐改变NSCLC治疗格局，但目前治疗效果有限，并且缺乏可靠的预测因子。我们既往发现，胆汁酸核受体FXR在NSCLC组织表达增高并促进肿瘤生长，然而FXR是否影响NSCLC转移，以及FXR在NSCLC免疫治疗中的作用目前仍不清楚。本项目研究发现：(1) FXR通过IL-6/IL-6ST/Jak2/STAT3信号通路促进NSCLC细胞迁移、侵袭和血管生成，并且FXR可直接激活IL-6ST和IL-6基因转录；(2) FXR抑制剂Z-guggulsterone (Z-GS)可抑制FXRhigh NSCLC肿瘤体内转移；(3) FXR抑制剂Z-GS通过部分激活Akt和ERK1/2信号通路、部分抑制FXR促进NSCLC表达PD-L1分子；(4) FXR可以预测PD-L1low/negative NSCLC患者使用“PD-1抗体+化疗”较好的治疗反应和生存期，并且FXR与肿瘤浸润CD8+ T细胞在NSCLC组织有负相关性。综上所述，本项目全面深入地揭示了FXR对NSCLC肿瘤转移的影响并探索了分子调控机制，丰富了理论知识。本项目通过体内外实验，首次评估了FXR抑制剂Z-GS对FXRhigh NSCLC肿瘤转移的治疗效果，以及Z-GS对NSCLC表达PD-L1分子的影响和分子调控机制，具备潜在临床转化应用价值。最后，本项目通过回顾性临床分析，发现肿瘤细胞表达FXR对于PD-L1low/negative NSCLC患者使用“PD-1抗体+化疗”治疗效果和生存期具有预测价值。