SARI suppresses colitis-associated cancer development by maintaining MCP-1-mediated tumour-associated macrophage recruitment
SARI suppresses colitis-associated cancer development by maintaining MCP-1-mediated tumour-associated macrophage recruitment
复制标题
SARI 通过维持 MCP-1 介导的肿瘤相关巨噬细胞募集来抑制结肠炎相关癌症的发展
DOI：
10.1111/jcmm.14699
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发表时间：
2019-10-02
影响因子：
5.3
通讯作者：
Deng, Hongxin
中科院分区：
文献类型：
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作者：
Dai, Lei;Liu, Yi;Deng, Hongxin
SARI（AP-1抑制因子，由IFN调节）通过促进细胞凋亡和抑制细胞增殖以及各种癌症中的肿瘤血管生成来损害肿瘤生长。然而，SARI在调节肿瘤相关炎症微环境中的作用仍然是难以捉摸的。本研究通过建立SARI缺陷小鼠和免疫重建小鼠结肠炎依赖性和非依赖性模型，探讨SARI在调节肿瘤相关炎症微环境和原发性结肠癌形成中的作用。结果表明，SARI缺乏症仅在结肠炎症存在的情况下促进结肠炎相关癌症（CAC）的发展。SARI抑制结肠组织中的肿瘤相关巨噬细胞（TAM）浸润，而骨髓细胞中的SARI缺乏在促进肠道肿瘤发生中没有观察到作用。机制研究表明，SARI下调p-STAT 1和STAT 1在结肠癌细胞中的表达，在CAC发展过程中抑制MCP-1/CCR 2轴激活。在结肠癌组织中，SARI表达与巨噬细胞浸润、MCP-1表达和p-STAT 1表达呈负相关。总之，我们的研究结果证明了SARI通过调节TAM浸润在结肠癌形成中的抑制作用。
SARI (suppressor of AP-1, regulated by IFN) impaired tumour growth by promoting apoptosis and inhibiting cell proliferation and tumour angiogenesis in various cancers. However, the role of SARI in regulating tumour-associated inflammation microenvironment is still elusive. In our study, the colitis-dependent and -independent primary model were established in SARI deficiency mice and immuno-reconstructive mice to investigate the functional role of SARI in regulating tumour-associated inflammation microenvironment and primary colon cancer formation. The results have shown that SARI deficiency promotes colitis-associated cancer (CAC) development only in the presence of colon inflammation. SARI inhibited tumour-associated macrophages (TAM) infiltration in colon tissues, and SARI deficiency in bone marrow cells has no observed role in the promotion of intestinal tumorigenesis. Mechanism investigations indicated that SARI down-regulates p-STAT1 and STAT1 expression in colon cancer cells, following inhibition of MCP-1/CCR2 axis activation during CAC development. Inverse correlations between SARI expression and macrophage infiltration, MCP-1 expression and p-STAT1 expression were also demonstrated in colon malignant tissues. Collectively, our results prove the inhibition role of SARI in colon cancer formation through regulating TAM infiltration.