Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in Toll-like receptor 2-deficient mice
Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in Toll-like receptor 2-deficient mice
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DOI：
10.1002/hep.25991
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发表时间：
2013-01-01
期刊：
影响因子：
13.5
通讯作者：
Hu, Zhuo-Wei
中科院分区：
文献类型：
--
作者：
Lin, Heng;Yan, Jun;Hu, Zhuo-Wei
肝细胞癌（HCC）是慢性炎症性肝病的终末期并发症，预后差。靶向Toll样受体（TLR）2可减弱肿瘤转移;我们假设阻断TLR 2也可能在减少肝癌发生中发挥关键作用。令人惊讶的是，我们发现TLR 2基因缺失增加了对二乙基亚硝胺（DEN）的易感性，DEN是一种可诱导HCC的遗传毒性致癌物质。事实上，TLR 2缺陷小鼠显示出HCC的致癌作用和进展的显著增加，如肿瘤结节大小、肿瘤体积和动物死亡的增加所示。对DEN诱导的HCC的易感性增强与对DEN诱导的肝损伤的免疫应答的广谱降低相关。我们发现TLR 2缺陷导致巨噬细胞浸润减少，凋亡信号调节激酶1（ASK 1）/ p38丝裂原活化蛋白激酶（p38 MAPK）/核因子κ B（NF-？B）信号传导，导致干扰素-γ（IFN-γ）表达降低，肿瘤坏死因子α（TNF-α）、白细胞介素（IL）-1 α/β、IL-6和Cxcl-2以及抑制自噬通量和增加氧化应激和肝组织中p62聚集。免疫网络中的缺陷导致抑制p21和p16/pRb依赖性衰老，这导致小鼠肝脏中增殖的增加和凋亡和自噬相关细胞死亡的减少。通过用IFN-γ治疗TLR 2缺陷小鼠恢复细胞衰老和自噬通量，一种辅助性T细胞1（Th 1）细胞因子和衰老和自噬的正调节剂，可以减弱与TLR 2缺陷动物相关的HCC的癌变和进展。结论：支持细胞衰老和自噬通量的免疫网络的丧失归因于TLR 2缺陷小鼠对DEN诱导的肝细胞癌发生和进展的易感性增强。这些发现可用于预防肝癌的发展。（肝脏学2013; 57：171-182）
Hepatocellular carcinoma (HCC) is a complication at the endstage of chronic inflammatory liver diseases with dismal prognosis. Targeting of Toll-like receptor (TLR) 2 attenuates tumor metastases; we hypothesized that blocking TLR2 might also play a crucial role in reducing hepatocarcinogenesis. Surprisingly, we found that the genetic deletion of TLR2 increased susceptibility to diethylnitrosamine (DEN), a genotoxic carcinogen that can induce HCC. Indeed, TLR2-deficient mice showed a significant increase in carcinogenesis and progression of HCC as indicated by increases in tumor nodule size, tumor volume, and animal death. The enhanced susceptibility to DEN-induced HCC was associated with a broad-spectrum reduction in the immune response to DEN-induced liver injury. We found that TLR2 deficiency caused a decrease in the infiltration of macrophages and an attenuation of apoptosis signal regulating kinase 1 (ASK1) / p38 mitogen-activated protein kinase (p38 MAPK) / nuclear factor kappa B (NF-?B) signaling, which led to a decrease in the expression of interferon-gamma (IFN-?), tumor necrosis factor alpha (TNF-a), interleukin (IL)-1a/beta, IL-6, and Cxcl-2 as well as suppression of autophagy flux and increases in oxidative stress and p62 aggregation in liver tissue. The defects in immune networks resulted in suppressed p21- and p16/pRb-dependent senescence, which caused an increase in proliferation and a decrease in apoptotic and autophagy-associated cell death in mouse livers. Restoring cellular senescence and autophagy flux by treating TLR2-deficient mice with IFN-?, a T helper 1 (Th1) cytokine and positive modulator of senescence and autophagy, could attenuate the carcinogenesis and progression of HCC associated with TLR2-deficient animals. Conclusion: The loss of immune networks supporting cellular senescence and autophagy flux is attributed to enhanced susceptibility to DEN-induced hepatocellular carcinogenesis and progression in TLR2-deficient mice. These findings may be used to prevent the development of liver cancer. (HEPATOLOGY 2013; 57: 171-182)