Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development.
Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development.
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DOI：
10.1016/j.bbrc.2015.07.078
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发表时间：
2015-09-18
影响因子：
3.1
通讯作者：
Ukomadu C
中科院分区：
文献类型：
--
作者：
Nayeb-Hashemi H;Desai A;Demchev V;Bronson RT;Hornick JL;Cohen DE;Ukomadu C
纤维蛋白原样蛋白 1 (Fgl1) 是一种主要由肝脏表达的蛋白，被认为是肝脏保护剂和肝细胞有丝分裂原。 Fgl1 表达在肝细胞癌 (HCC) 中降低，其缺失与低分化表型相关。为了更好地阐明 Fgl1 在肝癌发生中的作用，我们用二乙基亚硝胺治疗野生型或 Fgl1 缺失的小鼠，并监测肝细胞癌的发生率。我们发现缺乏 Fgl1 的小鼠患 HCC 的速度是野生型小鼠的两倍多。我们发现 Fgl1 缺失小鼠的肝细胞癌在分子上与野生型小鼠的肝细胞癌不同。在 Fgl1 缺失小鼠的肿瘤中，Akt 和哺乳动物雷帕霉素靶点 (mTOR) 下游靶点的激活增强。此外，假定的肝细胞癌肿瘤抑制因子存在矛盾的上调。含三联基序的蛋白 35 (Trim35) 和肿瘤坏死因子超家族 10b (Tnfrsf10b)。总而言之，这些发现表明 Fgl1 通过 Akt 依赖性机制在肝细胞癌中充当肿瘤抑制因子，并支持其作为 HCC 潜在治疗靶点的作用。
Fibrinogen like protein-1 (Fgl1) is a predominantly liver expressed protein that has been implicated as both a hepatoprotectant and a hepatocyte mitogen. Fgl1 expression is decreased in hepatocellular carcinoma (HCC) and its loss correlates with a poorly differentiated phenotype. To better elucidate the role of Fgl1 in hepatocarcinogenesis, we treated mice wild type or null for Fgl1 with diethyl nitrosamine and monitored for incidence of hepatocellular cancer. We find that mice lacking Fgl1 develop HCC at more than twice the rate of wild type mice. We show that hepatocellular cancers from Fgl1 null mice are molecularly distinct from those of the wild type mice. In tumors from Fgl1 null mice there is enhanced activation of Akt and downstream targets of the mammalian target of rapamycin (mTOR). In addition, there is paradoxical up regulation of putative hepatocellular cancer tumor suppressors; tripartite motif-containing protein 35 (Trim35) and tumor necrosis factor super family 10b (Tnfrsf10b). Taken together, these findings suggest that Fgl1 acts as a tumor suppressor in hepatocellular cancer through an Akt dependent mechanism and supports its role as a potential therapeutic target in HCC.