乙酰肝素酶动态调控肿瘤微环境在肝癌恶性转化中的分子机制

Heparanase is a mammalian endo-β -D-glucuronidase that specifically degrades heparan sulfate proteoglycans ubiquitously associated with cell surface and extracellular matrix. Over-expression of heparanase has been observed in a broad range of human cancers, where heparanase is believed to play an important role in promoting tumor metastasis and angiogenesis. Intriguingly, our recent work has discovered that the overexpression of heparanase in adjacent tumor tissue instead of that in tumor tissues is closely related to prognosis of liver cancer. Together with the fact that heparanase is secreted by cells and mainly functions at extracellular matrix, this finding raised the hypothesis that heparanase in cancer cells likely originates from stromal cells and heparanase has been implicated in cancer progression via modulating the cancer microenvironment when shuttling between tumor cells, stromal cells and extracellular matrix. To address this question, this project is to explore the role and mechanistic basis of heparanase in cancer progression using a three-dimensional co-culture based cellular system composed of tumor cells, stromal cells and extracellular matrix, where heparanase will be visualized using fluorescence. The significant contribution of heparanase into cancer progression will be explored in xenograft mouse models derived from co-cultured cells with ectopic expression of heparanase in stromal cells. This work will hopefully reveal the origins of overexpressed heparanase in wildly observed tumor tissues and more importantly will provide insights into the dynamic interaction between tumor microenvironment components.

乙酰肝素酶（Heparanase）是存在于细胞基质中的一种内源性β -葡萄糖醛酸酯酶。现有观点认为，肿瘤组织中乙酰肝素酶的高表达在肿瘤恶性化过程中扮演重要角色。不同于以往报道，我们前期发现肝癌的癌旁基质细胞中乙酰肝素酶高表达与肝癌的预后密切相关。本课题拟从临床研究结果出发，采用临床病人组织与实验动物相结合的模式，从细胞外基质、肿瘤细胞、和基质细胞三者构成的肿瘤炎性微环境网络互动的角度，通过多层次可视化的研究体系，追溯并探究肿瘤组织中乙酰肝素酶高表达的起源和成因，揭示乙酰肝素酶对肿瘤炎性微环境重塑的分子机制。研究结果对重新审视乙酰肝素酶在肝癌发生发展中的作用意义重大，对勾勒肿瘤与微环境之间的互为基础、互为因果的动态网络调控路线提供依据。

乙酰肝素酶（Heparanase，HPA）是存在于细胞外基质中的一种内源性β-葡萄糖醛酸酯酶。已有研究证明，乙酰肝素酶在肿瘤恶化过程中扮演重要角色，多种肿瘤组织中乙酰肝素酶的表达与肿瘤患者的预后密切相关。然而，肝癌中乙酰肝素酶的表达与肝癌恶化程度的相关性并不十分确定。本研究通过基础与临床相结合，围绕乙酰肝素酶在肝细胞癌发生发展过程中作用机制这一核心问题，具体聚焦三个方面：1）肝癌和/或癌旁组织中乙酰肝素酶表达水平与肝癌预后的相关性；2）乙酰肝素酶对肿瘤微环境的影响及其作用机制；3）靶向乙酰肝素酶的干预策略，开展了四部分的研究工作。本研究针对肝癌细胞中乙酰肝素酶的表达与肝癌恶化程度并不直接相关的问题，采用转化医学“临床—基础—临床”（B2B）的研究思路，以临床肝癌组织为研究样本，研究结果表明乙酰肝素酶在肝癌组织中为低表达，而在癌旁组织中有高表达，且这种高表达与肝癌术后预后呈负相关，是早期复发的重要相关因子。这部分研究结果提示乙酰肝素酶在癌旁组织的高表达可作为肝癌诊断和术后预后的生物标志物；细胞生物学系统研究表明，乙酰肝素酶高表达对于有利于肝肿瘤细胞侵袭的恶性环境的形成有重要作用，其作用机制是通过与与炎性因子互为因果、相互促进，逐级放大，不断恶化肿瘤炎性微环境，从而促进肝癌发生和恶化，这部分研究结果提示乙酰肝素酶是炎性微环境的重要穿梭因子或中间介质；最后对乙酰肝素酶抑制剂JG6作用机制的研究，发现了JG6抑制乙酰肝素酶内吞相关非酶活功能的新机制，拓展了靶向乙酰肝素酶的抗肿瘤策略。