Signal regulatory protein is associated with tumor-polarized macrophages phenotype switch and plays a pivotal role in tumor progression
Signal regulatory protein is associated with tumor-polarized macrophages phenotype switch and plays a pivotal role in tumor progression
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DOI：
10.1002/hep.26391
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发表时间：
2013-08-01
期刊：
影响因子：
13.5
通讯作者：
Wang, Hong-yang
中科院分区：
文献类型：
--
作者：
Pan, Yu-fei;Tan, Ye-xiong;Wang, Hong-yang
巨噬细胞(M)是肿瘤中浸润性白细胞的主要组成部分，根据微环境表现出不同的表型。近年来，我们发现在骨髓细胞上表达的抑制分子信号调节蛋白（signal regulatory protein， SIRP）在控制先天免疫激活中起着至关重要的作用。在这里，我们发现SIRP在从肝细胞癌（HCC）样本中分离的单核细胞/M上下调，而在瘤内M中其水平适度恢复。体外实验表明，当与肝癌细胞共培养时，SIRP在M上的表达显著降低。这种减少部分是由于肿瘤微环境中的可溶性因子。当M遇到肿瘤细胞时，SIRP的敲低（KD）延长了核因子κ B （NF-B）和PI3K-Akt通路的激活，导致M迁移、存活和促炎细胞因子产生能力增加。在肿瘤暴露的SIRP-KD M中，也观察到Stat3增强和Stat1磷酸化受损。SIRP-KD M过继转移通过重塑炎症微环境和促进血管生成，加速小鼠肝癌细胞在体内的生长。SIRP部分通过从IB激酶（IKK）和PI3K调控亚基p85 （PI3Kp85）中分离信号传感器Src同源2-含磷酸酪氨酸磷酸酶（SHP2）来实现这一点。结论：这些研究结果表明，SIRP在肝癌中是肿瘤极化M的重要调节剂，降低SIRP是肿瘤细胞改善其行为的一种新策略。因此，SIRP可以作为HCC治疗的潜在靶点。(肝脏病学58:680 2013;691)
Macrophages (M) are the major component of infiltrating leukocytes in tumors and exhibit distinct phenotypes according to the microenvironment. We have recently found that signal regulatory protein (SIRP), the inhibitory molecule expressed on myeloid cells, plays a critical role in controlling innate immune activation. Here, we identify that SIRP is down-regulated on monocytes/M isolated from peritumoral areas of hepatocellular carcinoma (HCC) samples, while its level is moderately recovered in intratumor M. In vitro assays demonstrate that SIRP expression is significantly reduced on M when cocultured with hepatoma cells. This reduction is partly due to the soluble factors in the tumor microenvironment. Knockdown (KD) of SIRP prolongs activation of nuclear factor kappa B (NF-B) and PI3K-Akt pathways as M encounter tumor cells, leading to an increased capacity of M for migration, survival, and proinflammatory cytokine production. Enhanced Stat3 and impaired Stat1 phosphorylation are also observed in tumor-exposed SIRP-KD M. Adoptive transfer with SIRP-KD M accelerates mouse hepatoma cells growth in vivo by remolding the inflammatory microenvironment and promoting angiogenesis. SIRP accomplishes this partly through its sequestration of the signal transducer Src homology 2-containing phosphotyrosine phosphatase (SHP2) from IB kinase (IKK) and PI3K regulatory subunit p85 (PI3Kp85). Conclusion: These findings suggest that SIRP functions as an important modulator of tumor-polarized M in hepatoma, and the reduction of SIRP is a novel strategy used by tumor cells to benefit their behavior. Therefore, SIRP could be utilized as a potential target for HCC therapy. (Hepatology 2013;58:680-691)