Peroxiredoxin I is important for cancer-cell survival in Ras-induced hepatic tumorigenesis

// Bing Han 1, 2 , Hye-Jun Shin 1 , In Seon Bak 1, 3 , Yesol Bak 1, 4 , Ye-Lin Jeong 1, 5 , Taeho Kwon 1 , Young-Ho Park 1 , Hu-Nan Sun 6 , Cheol-Hee Kim 2 , Dae-Yeul Yu 1 1 Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea 2 Department of Biology, Chungnam National University, Daejeon, 305-764, Korea 3 Department of Toxicology Evaluation, Graduate School of Preclinical Laboratory Science, Konyang University, Daejeon, 363-700, Korea 4 Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, 143-701, Korea 5 Department of Animal Biosystem Sciences, Chungnam National University, Daejeon, 305-764, Korea 6 College of Life Science and Biotechnology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China Correspondence to: Dae-Yeul Yu, email: dyyu10@kribb.re.kr Keywords: peroxiredoxin I, H-ras G12V , hepatic tumorigenesis, reactive oxygen species, gene regulation Received: February 11, 2016      Accepted: July 27, 2016      Published: August 10, 2016 ABSTRACT Peroxiredoxin I (Prx I), an antioxidant enzyme, has multiple functions in human cancer. However, the role of Prx I in hepatic tumorigenesis has not been characterized. Here we investigated the relevance and underlying mechanism of Prx I in hepatic tumorigenesis. Prx I increased in tumors of hepatocellular carcinoma (HCC) patients that aligned with overexpression of oncogenic H-ras. Prx I also increased in H-ras G12V transfected HCC cells and liver tumors of H-ras G12V transgenic (Tg) mice, indicating that Prx I may be involved in Ras-induced hepatic tumorigenesis. When Prx I was knocked down or deleted in HCC-H-ras G12V cells or H-ras G12V Tg mice, cell colony or tumor formation was significantly reduced that was associated with downregulation of pERK pathway as well as increased intracellular reactive oxygen species (ROS) induced DNA damage and cell death. Overexpressing Prx I markedly increased Ras downstream pERK/FoxM1/Nrf2 signaling pathway and inhibited oxidative damage in HCC cells and H-ras G12V Tg mice. In this study, we found Nrf2 was transcriptionally activated by FoxM1, and Prx I was activated by the H-ras G12V /pERK/FoxM1/Nrf2 pathway and suppressed ROS-induced hepatic cancer-cell death along with formation of a positive feedback loop with Ras/ERK/FoxM1/Nrf2 to promote hepatic tumorigenesis.