Circulating AIM Prevents Hepatocellular Carcinoma through Complement Activation
Circulating AIM Prevents Hepatocellular Carcinoma through Complement Activation
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DOI：
10.1016/j.celrep.2014.08.058
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发表时间：
2014-10-09
期刊：
影响因子：
8.8
通讯作者：
Miyazaki, Toru
中科院分区：
文献类型：
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作者：
Maehara, Natsumi;Arai, Satoko;Miyazaki, Toru
肝细胞癌（HCC）是一种广泛的致命性疾病，是癌症死亡的第三大常见原因。在这里，我们展示了循环蛋白AIM的有效抗HCC作用。在脂肪细胞中，AIM被掺入正常肝细胞中，在那里它干扰脂质储存。相比之下，AIM在HCC细胞表面上积累，并通过灭活补体激活的多种调节剂来激活补体级联。这种反应特别在AIM结合的HCC细胞中引起坏死细胞死亡。因此，AIM（-/-）小鼠对脂肪变性相关的HCC发展高度敏感，而AIM（+/+）小鼠尽管响应于长期高脂肪饮食而具有相当的肝脏炎症和纤维化，但没有发展该疾病。给药AIM可预防AIM（-/-）小鼠的肿瘤发展，并且在AIM（-/-）小鼠中二乙基亚硝胺诱导的HCC比野生型小鼠更显著。这些发现可能是基于AIM的HCC新治疗策略的基础。
Hepatocellular carcinoma (HCC) is a widespread fatal disease and the third most common cause of cancer deaths. Here, we show the potent anti-HCC effect of the circulating protein AIM. As in adipocytes, AIM is incorporated into normal hepatocytes, where it interferes with lipid storage. In contrast, AIM accumulates on the HCC cell surface and activates the complement cascade via inactivating multiple regulators of complement activation. This response provokes necrotic cell death specifically in AIM-bound HCC cells. Accordingly, AIM(-/-) mice were highly susceptible to steatosis-associated HCC development, whereas no AIM(+/+) mouse developed the disease despite comparable liver inflammation and fibrosis in response to a long-term high-fat diet. Administration of AIM prevented tumor development in AIM(-/-) mice, and HCC induction by diethylnitrosamine was more prominent in AIM(-/-) than wild-type mice. These findings could be the basis for novel AIM-based therapeutic strategies for HCC.