FABP4 deactivates NF-κB-IL1α pathway by ubiquitinating ATPB in tumor-associated macrophages and promotes neuroblastoma progression.
FABP4 deactivates NF-κB-IL1α pathway by ubiquitinating ATPB in tumor-associated macrophages and promotes neuroblastoma progression.
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DOI：
10.1002/ctm2.395
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发表时间：
2021-04
影响因子：
10.6
通讯作者：
He J
中科院分区：
文献类型：
--
作者：
Miao L;Zhuo Z;Tang J;Huang X;Liu J;Wang HY;Xia H;He J
神经母细胞瘤（NB）是最常见和最致命的儿科实体瘤。靶向和重新激活肿瘤相关巨噬细胞（TAM）对于逆转免疫抑制状态和刺激免疫防御以发挥杀肿瘤功能是必要的。然而，关于TAM在NB进展中的功能和调节的研究仍然有限。TAMs中的脂肪酸结合蛋白4（FABP 4）与NB的晚期临床分期和不良组织学相关。FABP 4介导的巨噬细胞增加NB细胞的迁移、侵袭和肿瘤生长。在机械上，FABP 4可以直接与ATPB结合，加速ATPB在巨噬细胞中的泛素化。因此ATP水平降低可使NF-κB/RelA-IL 1 α通路失活，随后导致巨噬细胞重编程为抗炎表型。我们还证明了FABP 4增强的迁移和侵袭被IL 1 α阻断抗体显著抑制。此外，循环FABP 4也与NB的临床分期相关。我们的研究结果表明，FABP 4介导的巨噬细胞可能通过泛素化ATPB使NF-κB-IL 1 α通路失活，从而促进NB细胞的增殖和迁移表型。这项研究揭示了FABP 4介导的巨噬细胞在NB发展中的病理学和生物学作用，并展示了靶向巨噬细胞中的FABP 4用于NB治疗的新应用。FABP 4在巨噬细胞中的表达与神经母细胞瘤的晚期临床分期和不良组织学相关。巨噬细胞中的FABP 4增加神经母细胞瘤细胞的迁移、侵袭和肿瘤生长。巨噬细胞中的FABP 4可能通过泛素化ATPB使NF-κB-IL 1 α通路失活，从而促进神经母细胞瘤细胞的增殖和迁移表型。
Neuroblastoma (NB) is the most common and deadliest pediatric solid tumor. Targeting and reactivating tumor‐associated macrophages (TAMs) is necessary for reversing immune suppressive state and stimulating immune defense to exert tumoricidal function. However, studies on the function and regulation of TAMs in NB progression are still limited. Fatty acid binding protein 4 (FABP4) in TAMs was correlated with advanced clinical stages and unfavorable histology of NB. FABP4‐mediated macrophages increased migration, invasion, and tumor growth of NB cells. Mechanically, FABP4 could directly bind to ATPB to accelerate ATPB ubiquitination in macrophages. The consequently decreased ATP levels could deactivate NF‐κB/RelA‐IL1α pathway, which subsequently results in macrophages reprogrammed to an anti‐inflammatory phenotype. We also demonstrated that FABP4‐enhanced migration and invasion were significantly suppressed by IL1α blocking antibody. Furthermore, circulating FABP4 was also associated with the clinical stages of NB. Our findings suggest that FABP4‐mediated macrophages may promote proliferation and migration phenotypes in NB cells through deactivating NF‐κB‐IL1α pathway by ubiquitinating ATPB. This study reveals the pathologic and biologic role of FABP4‐mediated macrophages in NB development and exhibits a novel application of targeting FABP4 in macrophages for NB treatment. FABP4 in macrophages expression is correlated with advanced clinical stages and unfavorable histology of neuroblastoma. FABP4 in macrophages increases migration, invasion, and tumor growth of neuroblastoma cells. FABP4 in macrophages may promote proliferation and migration phenotypes in neuroblastoma cells through deactivating NF‐κB‐IL1α pathway by ubiquitinating ATPB.
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DOI：
10.1073/pnas.1512832112
发表时间：
2015-12-15
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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DOI：
10.4137/cmc.s17067
发表时间：
2014
期刊：
Clinical Medicine Insights. Cardiology
影响因子：
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作者：
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影响因子：
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