IGFBP7 Deletion Promotes Hepatocellular Carcinoma.
IGFBP7 Deletion Promotes Hepatocellular Carcinoma.
复制标题
DOI：
10.1158/0008-5472.can-16-2885
复制
发表时间：
2017-08-01
期刊：
影响因子：
11.2
通讯作者：
Sarkar D
中科院分区：
文献类型：
--
作者：
Akiel M;Guo C;Li X;Rajasekaran D;Mendoza RG;Robertson CL;Jariwala N;Yuan F;Subler MA;Windle J;Garcia DK;Lai Z;Chen HH;Chen Y;Giashuddin S;Fisher PB;Wang XY;Sarkar D
IGF信号传导的激活是多种癌症（包括肝细胞癌（HCC））中的主要致癌事件。在这种情况下，胰岛素样生长因子结合蛋白IGFBP 7通过结合IGF-1受体（IGF-1 R）抑制IGF信号传导，作为候选肿瘤抑制因子发挥作用。IGFBP 7通过抑制血管生成和诱导癌症特异性衰老和凋亡来消除肿瘤。在这里，我们报告说，Igfbp 7缺陷的小鼠表现出组成性活跃的IGF信号，呈现促炎和免疫抑制微环境和自发性肝和肺肿瘤发生率增加的致癌剂治疗的科目。Igfbp 7缺失增加了肝细胞和小鼠胚胎成纤维细胞的增殖并降低了衰老，这种作用可通过IGF-1受体抑制剂治疗来阻断。在Igfbp 7 −/−小鼠肝脏中观察到调节免疫监视的基因的显著抑制，这与Igfbp 7 −/−树突状细胞对抗原交叉呈递的显著抑制有关。相反，IGFBP 7过表达抑制了同基因免疫活性小鼠中HCC细胞的生长。CD 4+或CD 8 + T淋巴细胞的耗竭消除了这种生长抑制，将其鉴定为免疫介导的应答。我们的研究结果定义了IGFBP 7抑制HCC的多效性机制的免疫组分。此外，他们提供了IGFBP 7作为HCC免疫管理治疗靶点的基于遗传的临床前概念证明。
Activation of IGF signaling is a major oncogenic event in diverse cancers, including hepatocellular carcinoma (HCC). In this setting, the insulin-like growth factor binding protein IGFBP7 inhibits IGF signaling by binding the IGF-1 receptor (IGF-1R), functioning as a candidate tumor suppressor. IGFBP7 abrogates tumors by inhibiting angiogenesis and inducing cancer-specific senescence and apoptosis. Here we report that Igfbp7-deficient mice exhibit constitutively active IGF signaling, presenting with pro-inflammatory and immunosuppressive microenvironments and spontaneous liver and lung tumors occurring with increased incidence in carcinogen-treated subjects. Igfbp7 deletion increased proliferation and decreased senescence of hepatocytes and mouse embryonic fibroblasts, effects that were blocked by treatment with IGF-1 receptor inhibitor. Significant inhibition of genes regulating immune surveillance was observed in Igfbp7−/− murine livers, which was associated with a marked inhibition in antigen cross-presentation by Igfbp7−/− dendritic cells. Conversely, IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immunocompetent mice. Depletion of CD4+ or CD8+ T lymphocytes abolished this growth inhibition, identifying it as an immune-mediated response. Our findings define an immune component of the pleiotropic mechanisms through which IGFBP7 suppresses HCC. Furthermore, they offer a genetically based preclinical proof of concept for IGFBP7 as a therapeutic target for immune management of HCC.