对氧磷酶2通过肿瘤相关巨噬细胞对肿瘤血管生成影响的研究

Paraoxonase 2 is one of proteins against stress. Exogenous stimulus could lead ROS elevation from mitochondria，which could be attenuated by paraoxonase 2. So paraoxonae 2 has the function of anti-apoptosis and anti-ER stress. In present studies, paraoxonase has been considered to stabilize cancer cells by anti-apoptosis, which serve as the opposing factor of radiotherapy and chemotherapy for cancer. Our pre-study have shown that paraoxonase 2 participate macrophage polarization. Accumulated studies indicated that TAM were characterized as M2 macrophage, which could promote angiogenesis in carcinoma. Based on these evidence, we deduced that PON2 could interfere angiogenesis of tumor by influence in macrophage polarization. So we evaluate the effects imposed by PON2 on angiogenesis of tumor by macrophage in vivo and in vitro. Moreover, concluded from our pre-study and accumulated reports, we believed that PON2-/- in macrophage could elevate the expression of CHOP, which could promote the M2 macrophage polarization by influence in the expression of SOCS3 and its related factors. In this study, we will try to elucidate the mechanism that CHOP regulate the expression of SOCS3. With the conclusions of this study, the understanding of PON2 will be refreshed for its role in the pathogenesis, progression and therapy of cancer. More importantly, conclusions from this study will refresh the supports for the development of targeting medicines.

对氧磷酶2是体内重要的抗应激分子，可以降低外源刺激导致的线粒体内活性氧的升高，抑制内质网应激及细胞凋亡。目前研究认为对氧磷酶2在肿瘤形成后可以稳定肿瘤细胞，抑制其凋亡，对肿瘤的放化疗具有对抗作用。前期研究发现，在体外对氧磷酶2参与巨噬细胞的极化过程。以往研究显示肿瘤相关巨噬细胞具有M2型巨噬细胞的特征，可以促进肿瘤血管的生成。由此，本研究推断，对氧磷酶2可能通过影响巨噬细胞的极化而干预肿瘤血管的生成。研究拟从动物和细胞水平，考察巨噬细胞在对氧磷酶2缺失后对肺肿瘤中血管生成的影响。结合前期结果和以往研究，发现巨噬细胞中对氧磷酶2缺失导致CHOP的表达升高，进一步影响了SOCS3相关信号通路及分子的表达，促进巨噬细胞M2型的极化。本研究拟进一步阐述CHOP对SOCS3通路的调控机制。本研究有助于重新定位对氧磷酶2在肿瘤发生、发展以及治疗中的地位，为靶向药物的开发提供新的理论依据。