The Association of Peroxiredoxin 4 with the Initiation and Progression of Hepatocellular Carcinoma
The Association of Peroxiredoxin 4 with the Initiation and Progression of Hepatocellular Carcinoma
复制标题
DOI：
10.1089/ars.2017.7426
复制
发表时间：
2018-06-11
影响因子：
6.6
通讯作者：
Yamada, Sohsuke
中科院分区：
文献类型：
--
作者：
Guo, Xin;Noguchi, Hirotsugu;Yamada, Sohsuke
过氧化物氧还蛋白4（Peroxiredoxin 4，PRDX 4）是过氧化物氧还蛋白家族的一员。以前，我们报道PRDX 4可以通过降低局部和全身活性氧（ROS）水平来抑制非酒精性脂肪性肝炎的发生和进展。氧化应激被认为是肝癌发生的关键因素，在肝细胞癌（HCC）中也发现了高水平的ROS。在这里，我们的目的是调查PRDX 4在HCC的发生和发展中的作用。结果：在这项研究中，对于肝癌的发生，野生型（WT），PRDX 4基因敲除（PRDX 4（-/y）），和人PRDX 4转基因（hPRDX 4（+/+））小鼠每周腹腔注射二乙基亚硝胺25周。PRDX 4（-/y）小鼠的HCC发病率高于WT或hPRDX 4（+/+）小鼠。与WT小鼠相比，hPRDX 4（+/+）小鼠的肝内和循环氧化应激以及肝脏中的炎性细胞浸润明显减少。此外，在我们的队列研究中，与PRDX 4高表达的人HCC标本相比，PRDX 4低表达的人HCC标本具有较高的ROS水平和高度恶性表型，这与总生存率降低相关。然而，在人HCC细胞系中，PRDX 4敲低导致细胞内ROS水平迅速升高，并抑制细胞增殖，诱导细胞死亡。我们的研究结果清楚地表明PRDX 4在HCC的发生中具有抑制作用，但在HCC的发生中具有双重抑制作用。在HCC进展中的（抑制或促进）作用，提示PRDX 4激活剂或抑制剂作为HCC的不同阶段和表型的治疗的潜在效用。
Aims: Peroxiredoxin 4 (PRDX4) is a member of the peroxiredoxin family of antioxidant enzymes. Previously, we reported that PRDX4 can restrain the initiation and progression of nonalcoholic steatohepatitis by reducing local and systemic reactive oxygen species (ROS) levels. Oxidative stress is recognized as a key factor in hepatocarcinogenesis, and a high ROS level has also been found in hepatocellular carcinoma (HCC). Here, our aim is to investigate roles of PRDX4 in the initiation and progression of HCC.Results: In this study, for hepatocarcinogenesis, wild-type (WT), PRDX4 knockout (PRDX4(-/y)), and human PRDX4 transgenic (hPRDX4(+/+)) mice were given a weekly intraperitoneal injection of diethylnitrosamine for 25 weeks. The HCC incidence was higher in PRDX4(-/y) mice than in WT or hPRDX4(+/+) mice. Intrahepatic and circulating oxidative stress and inflammatory cell infiltration in the liver were obviously decreased in hPRDX4(+/+) mice, compared with WT mice. Furthermore, in our cohort study, human HCC specimens with low expression of PRDX4 had higher ROS levels and a highly malignant phenotype, which was associated with a reduced overall survival, compared with those with high PRDX4 expression. However, in human HCC cell lines, PRDX4 knockdown led to a rapidly increased intracellular ROS level and suppressed cell proliferation, inducing cell death.Innovation and Conclusion: Our results clearly indicate that PRDX4 has an inhibitory effect in the initiation of HCC, but a dual (inhibitory or promoting) role in the progression of HCC, suggesting the potential utility of PRDX4 activators or inhibitors as therapy for different stages and phenotypes of HCC.