title: Peroxiredoxin I is important for cancer-cell survival in Ras-induced hepatic tumorigenesis.
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-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.
authors: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea.|Department of Biology, Chungnam National University, Daejeon, 305-764, Korea.
authors: Bing
authors: B
authors: Han
authors: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea.
authors: Hye-Jun
authors: HJ
authors: Shin
authors: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea.|Department of Toxicology Evaluation, Graduate School of Preclinical Laboratory Science, Konyang University, Daejeon, 363-700, Korea.
authors: In Seon
authors: IS
authors: Bak
authors: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea.|Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, 143-701, Korea.
authors: Yesol
authors: Y
authors: Bak
authors: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea.|Department of Animal Biosystem Sciences, Chungnam National University, Daejeon, 305-764, Korea.
authors: Ye-Lin
authors: YL
authors: Jeong
authors: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea.
authors: Taeho
authors: T
authors: Kwon
authors: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea.
authors: Young-Ho
authors: YH
authors: Park
authors: College of Life Science and Biotechnology, Heilongjiang Bayi Agricultural University, Daqing, 163319, China.
authors: Hu-Nan
authors: HN
authors: Sun
authors: Department of Biology, Chungnam National University, Daejeon, 305-764, Korea.
authors: Cheol-Hee
authors: CH
authors: Kim
authors: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea.
authors: Dae-Yeul
authors: DY
authors: Yu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054464:Peroxiredoxins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D017382:Reactive Oxygen Species; D054464:Peroxiredoxins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: H-rasG12V; gene regulation; hepatic tumorigenesis; peroxiredoxin I; reactive oxygen species