Peroxiredoxin I is important for cancer-cell survival in Ras-induced hepatic tumorigenesis
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Bing Han1,2, Hye-Jun Shin1, In Seon Bak1,3, Yesol Bak1,4, Ye-Lin Jeong1,5, Taeho Kwon1, Young-Ho Park1, Hu-Nan Sun6, Cheol-Hee Kim2, Dae-Yeul Yu1
1Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea
2Department of Biology, Chungnam National University, Daejeon, 305-764, Korea
3Department of Toxicology Evaluation, Graduate School of Preclinical Laboratory Science, Konyang University, Daejeon, 363-700, Korea
4Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, 143-701, Korea
5Department of Animal Biosystem Sciences, Chungnam National University, Daejeon, 305-764, Korea
6College of Life Science and Biotechnology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China
Dae-Yeul Yu, email: email@example.com
Keywords: peroxiredoxin I, H-rasG12V, hepatic tumorigenesis, reactive oxygen species, gene regulation
Received: February 11, 2016 Accepted: July 27, 2016 Published: August 10, 2016
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-rasG12V transfected HCC cells and liver tumors of H-rasG12V 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-rasG12V cells or H-rasG12V 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-rasG12V Tg mice. In this study, we found Nrf2 was transcriptionally activated by FoxM1, and Prx I was activated by the H-rasG12V/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.
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