A pro-tumorigenic function of S100A8/A9 in carcinogen-induced hepatocellular carcinoma
A pro-tumorigenic function of S100A8/A9 in carcinogen-induced hepatocellular carcinoma
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DOI：
10.1016/j.canlet.2015.09.005
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发表时间：
2015-12-28
期刊：
影响因子：
9.7
通讯作者：
Angel, Peter
中科院分区：
文献类型：
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作者：
De Ponti, Aurora;Wiechert, Lars;Angel, Peter
人肝细胞癌（HCC）是一种异质性疾病，由不同的危险因素驱动，具有不同的临床病理特征和预后。流行病学和实验数据表明，与损伤相关的分子模式分子S100A8和S100A9形成一种称为钙保护蛋白的异源二聚体，可能在HCC的发展中起关键作用。然而，在炎症和肝硬化驱动的小鼠模型中，S100a9的缺失并未显示出肝脏肿瘤发生的任何损害，这很可能是由于其他炎症细胞因子的功能代偿。在这里，我们研究了钙保护蛋白消融对二乙基亚硝胺治疗小鼠的影响，二乙基亚硝胺是一种致癌物质驱动的HCC模型，模拟了在没有明显慢性炎症和组织损伤的情况下由急性肝损伤引起的癌症发展。我们发现，在缺乏S100A8/A9的情况下，肿瘤细胞的增殖能力减弱，导致肿瘤大小明显减小。我们的研究结果表明，钙保护蛋白是非炎症驱动的肝肿瘤进展所必需的，可能代表了治疗非肝硬化肝脏中形成的HCC的治疗靶点。2015爱思唯尔爱尔兰有限公司版权所有。
Human hepatocellular carcinoma (HCC) is a heterogeneous disease, driven by different risk factors and presenting diverse clinicopathological features and outcomes. Epidemiological and experimental data indicate that the damage-associated molecular pattern molecules S100A8 and S100A9, forming a heterodimer called calprotectin, might be critically involved in HCC development. However, deletion of S100a9 in an inflammation- and cirrhosis-driven mouse model did not show any impairment in liver tumorigenesis, most likely due to functional compensation by other inflammatory cytokines. Here, we investigated the effect of calprotectin ablation in mice treated with diethylnitrosamine, a carcinogen-driven HCC model mimicking cancer development caused by acute liver damage in the absence of prominent chronic inflammation and tissue damage. We found that tumor cell proliferation was diminished in the absence of S100A8/A9, leading to significant reduction of tumor size.Our results demonstrate that calprotectin is required for the progression of non-inflammation driven liver tumor and might represent a therapeutic target for the treatment of HCC formed in non-cirrhotic liver. (C) 2015 Elsevier Ireland Ltd. All rights reserved.