PON1通过SR-BI减少肿瘤相关巨噬细胞募集和M2极化抑制肝癌的侵袭和转移

PON1 (paraoxonase 1) belongs to a family of calcium-dependent hydrolase proteins, mainly synthesized in liver. Serum PON1 concentration and activity were inversely associated with cardiac-vascular disease. Our previous research based on proteomics found that the serum concentration of PON1 significantly decreased in the hepatocellular carcinoma (HCC) patients with vascular invasion as compared with those without vascular invasion, and the tumoral expression also decreased. Downregulation of PON1 expression in tumoral tissue was a maker of poor prognosis for the patients who underwent curtive liver resection for HCC. In vitro studies, we found that overexpression of PON1 in hepatoma cells did not suppress the proliferation and invasion of these cells, however, in vivo tumor growth was significantly restrained when these cells were implanted into the liver of nude mice. These results indicated that PON1 suppressed tumor progression as a non-cell-autonomous manner, that is, in a way by modulating the tumor microenvironment and then inhibited tumor progress indirectly but not changing the tumor cells directly. In vivo studies also revealed that PON1 significantly suppress intra-tumoral macrophage infiltration, indicating that targeting tumor-associated macrophages and inhibition of the M2 phenotype could be one of the mechanisms. In the studies of atherosclerosis, SR-BI (scavenger receptor class B type I) was believed to be the key molecule that mediated the macrophage-modulating effects of PON1, by down-regulating the expression of SR-BI, PON1 inhibited the differentiation, recruitment of macrophages and the formation of form cells, which is a tissue specific macrophages. In this project, we are aiming to verify the anti-invasive effects of PON1 in HCC, and study whether SR-BI–mediated depletion of macrophages and M2 polarization was the key mechanism. These studies could provide a novel strategy for the treatment for tumor metastasis in HCC.

PON1（对氧磷酯酶-1）是由肝脏合成的钙离子依赖性芳香酯酶，其血清浓度及活性在心血管等疾病中明显下降。申请者前期基于蛋白组学的研究发现合并血管侵犯的肝癌患者血清中及肿瘤组织中PON1的水平显著下降，PON1低表达的患者预后较差。预实验中，我们发现过表达PON1的肝癌细胞在体外的增殖及侵袭能力无明显下降，但接种于裸鼠原位后，肿瘤生长明显被抑制，提示PON1通过影响肝癌微环境间接抑制肿瘤进展。动物实验中，PON1表达可显著抑制巨噬细胞（MΦ）浸润，提示MΦ浸润和M2型极化减少可能是PON1抑制肝癌进展的机制之一。动脉粥样硬化相关研究提示PON1可能通过SR-BI（B类I型清道夫受体）表达抑制单核-MΦ分化、募集和减少泡沫细胞形成。本项目中，我们拟通过体内外实验及临床标本研究，探索SR-BI介导的MΦ募集减少和M2极化抑制是否为其中的关键机制，通过对该机制的深入研究，为肝癌转移治疗提供新思路。

PON1（对氧磷酯酶-1）是由肝脏合成的钙离子依赖性芳香酯酶，其血清浓度及活性在心血管等疾病中明显下降。前期基于蛋白组学的研究发现合并血管侵犯的肝癌患者血清中及肿瘤组织中PON1的水平显著下降，PON1低表达的患者预后较差。进一步研究发现过表达PON1的肝癌细胞在体外的增殖及侵袭能力无明显下降，但接种于裸鼠原位后，肿瘤生长明显被抑制，提示PON1通过影响肝癌微环境间接抑制肿瘤进展。动物实验中，PON1表达可显著抑制巨噬细胞（MΦ）浸润，揭示MΦ浸润和M2型极化减少是PON1抑制肝癌进展的机制。机制研究发现PON1通过SR-BI表达抑制单核-MΦ分化。申请者通过体内外实验及临床标本研究，深入解析PON1在肝癌微环境的作用，为肝癌转移治疗提供新思路。