低氧下白细胞介素-1β在肿瘤相关巨噬细胞介导肝癌上皮间质化中的作用研究

Hypoxic environment is a hallmark of solid cancer including hepatocellular carcinoma (HCC). Hypoxia promotes HCC progression via miscellaneous ways, one of which is epithelial-mesenchymal transition (EMT). More importantly, hypoxia does not only affect HCC cells but also impact other cells within tumor such as tumor-associated macrophage (TAM). Former studies predominantly focused on the effects of hypoxia on tumor cells, while the regulation of HCC cells by other cells within tumor under hypoxic condition was largely unknown. Our previous studies found that hypoxia could induce EMT in HCC cells (Carcinogenesis 2013) and persistent secretion of interleukin-1β (IL-1β) by TAM (Cancer Research 2012). Further study revealed that IL-1β induced EMT-like changes in HCC cells. In this project, we will investigate the role of IL-1β in TAM-mediated EMT in HCC. By using recombinant IL-1β and HCC mouse models, we will study the mechanisms by which TAM regulates HCC under hypoxic condition in vitro and in vivo. It is an in-depth continuation of our previous study. The results would contribute to further understanding of inflammation-tumor signal under hypoxic condition and provide novel strategies for HCC treatment.

低氧微环境是肝癌等实体瘤的重要特征。上皮间质化（EMT）是低氧促进肝癌进展的重要方式。低氧不仅影响肝癌细胞，还影响肿瘤间质中的肿瘤相关巨噬细胞（TAM）。既往研究多着眼于低氧对肿瘤细胞本身的作用，对低氧微环境下肿瘤间质中其他细胞对肝癌细胞的调节机制所知甚少。我们前期研究证实低氧可诱导肝癌细胞发生EMT（Carcinogenesis），以及TAM释放大量白介素-1β（IL-1β；Cancer Res）；后续研究又发现IL-1β可引起肝癌细胞发生EMT样改变。本课题拟在前期研究基础上，以IL-1β为切入点，以TAM对肝癌细胞EMT调节作用为研究重点，利用重组IL-1β因子和肝癌动物模型，采用体内外实验，研究低氧微环境下TAM介导肝癌EMT的作用及其机制。研究结果有可能解释IL-1β在肝癌进展中的作用并进一步丰富低氧微环境下“炎-癌”生物信号理论，为开发新的肝癌防治手段提供理论依据。

低氧及炎症是肝癌微环境的重要特征。上皮间质转化是低氧促进肝癌进展的重要方式。既往研究多关注与低氧对肝癌细胞的影响，而低氧对肝癌微环境中肿 瘤相关巨噬细胞的调节机制仍有待研究。本研究对肝癌“低氧-炎症” 微环境中肿瘤相关巨噬细胞与肝癌细胞相互作用的机制进行探讨。研究发现，肿瘤微环境中低氧及坏死细胞碎片分别可通过 Hif-1α 及 TLR4/TRIF/p-NF-κB途径促进巨噬细胞合成及分泌 IL-1β，造成微环境持续炎性改变，进而由 IL-1β/ COX-2/Hif-1α 介导促进肝癌 EMT 及转移。提示 IL-1β 是肝癌微环境中耦联 TAMs 及肝癌细胞的重要炎症分子，为以抗炎为策略的肿瘤辅助治疗提供了理论依据。