白介素37调控肺癌血管内皮细胞EndMT的分子机制研究

Lung cancer is considered as the most life-threatening cancer worldwide. Metastases are the most important reasons for lung cancer being difficult to cure or controlled with treatment. Tumor angiogenesis sustains primary tumor growth and provides a route for metastatic escape. In tumor microenvironment, endothelial cells that undergo endothelial-to-mesenchymal transition (EndMT) are permissive to tumor cell transmigration, leading to increased metastasis. Studies showed that TGF-β is a critical regulator of tumor angiogenesis and EndMT. We have previously reported that interleukin-37 (IL-37) is an important pro-angiogenic factor that promotes angiogenesis through TGF-β signaling pathway. We further found that IL-37 promotes tumor angiogenesis and metastasis in mouse xenograft tumor model and induces EndMT in endothelial cells. Based on previous work, this project aims to investigate the molecular mechanism underlying the regulatory effect of IL-37 on EndMT in lung cancer using genetically engineered mouse models of lung cancer and clinical samples. We will next investigate how IL-37 interact with TGF-β receptor complex and modulates TGF-β downstream signaling pathway. Finally, we will determine how TGF-β receptor mediates the regulatory effect of IL-37 on tumor angiogenesis and EndMT. The results will provide important information for the understanding of the regulatory mechanism underlying IL-37 signaling in tumor angiogenesis and EndMT in lung cancer, and further provide theoretical basis for prevention and therapeutics of lung cancer.

肺癌是威胁人类健康的第一大肿瘤性疾病，转移则是肺癌难以治愈及威胁生命的最重要原因。肿瘤血管是促进肿瘤生长及转移的关键因素，在肿瘤微环境诱导下可发生内皮间质转化（EndMT），使肿瘤细胞易于通过血管转移。研究表明TGF-β是调控肿瘤血管生成及EndMT的关键因子。我们团队报道，白介素37（IL-37）是重要促血管生成因子，可通过激活TGF-β信号通路调节血管生成。进一步前期工作表明，IL-37促进小鼠移植瘤血管生成及肿瘤转移，并可诱导血管内皮细胞间质化标志上调。本项目拟在原来的工作基础上，利用小鼠自发肺癌模型和临床样本，深入探讨IL-37对肺癌血管内皮细胞EndMT的调控机制，明确IL-37调节TGF-β受体信号通路的分子机制，阐明TGF-β受体如何介导IL-37对肿瘤血管生成及EndMT的调控作用。本项目的完成将加深IL-37对肺癌血管生成及功能调控机制的理解，为肺癌治疗提供重要依据。

肝癌是死亡率非常高的恶性肿瘤之一。转移是肿瘤难以治愈及威胁生命的重要原因。内皮间质转化（EMT）被认为是导致肿瘤侵袭和转移的重要机制。白介素37是相对较新的白介素1家族成员，具有重要的免疫调节作用，其在肿瘤发病中的作用近年来受到关注。但其在肝癌进展和转移中的作用仍不清楚。该研究中，我们探索了IL-37在肝癌中的作用。我们发现，IL-37重组蛋白在较低浓度下通过Snail/Akt信号通路促进肿瘤生长和EMT转化。我们在体外实验中发现低浓度IL-37能够促进肝癌细胞增殖、克隆形成、迁移、侵袭等功能。我们在体内移植瘤模型中发现IL-37对小鼠肝癌细胞移植瘤生长和转移的促进作用。我们进一步在小鼠体内肿瘤转移模型中验证了IL-37对肝癌细胞肺组织转移的促进作用。分子机制方面，我们发现，IL-37能够促进Snail转录因子的表达和细胞核定位，并且IL-37能够激活Akt信号通路，抑制Akt激活能够阻断IL-37引起的SNAIL蛋白水平增加以及细胞侵袭能力的增加。我们的研究显示白介素 37 是新型促进肝癌进展和转移的重要因子。