Xin Guo1,2,3, Hirotsugu Noguchi4, Naoki Ishii5, Takujiro Homma5, Taiji Hamada3, Tsubasa Hiraki3, Jing Zhang1, Kei Matsuo3, Seiya Yokoyama3, Hiroaki Ishibashi6, Tomoko Fukushige7, Takuro Kanekura7, Junichi Fujii5, Hidetaka Uramoto8, Akihide Tanimoto3, Sohsuke Yamada1,3. 1. 1 Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, Japan. 2. 2 Laboratory of Pathology, Hebei Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China. 3. 3 Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. 4. 4 Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. 5. 5 Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata, Japan. 6. 6 Department of Oral and Maxillofacial Surgery, Kanazawa Medical University, Ishikawa, Japan. 7. 7 Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. 8. 8 Department of Thoracic Surgery, Kanazawa Medical University, Ishikawa, Japan.
Abstract
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.
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 humanPRDX4 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.