Peroxiredoxin II promotes hepatic tumorigenesis through cooperation with Ras/Forkhead box M1 signaling pathway.
The current study was carried out to define the involvement of Peroxiredoxin (Prx) II in progression of hepatocellular carcinoma (HCC) and the underlying molecular mechanism(s). Expression and function of Prx II in HCC was determined using H-ras(G12V)-transformed HCC cells (H-ras(G12V)-HCC cells) and the tumor livers from H-ras(G12V)-transgenic (Tg) mice and HCC patients. Prx II was upregulated in H-ras(G12V)-HCC cells and H-ras(G12V)-Tg mouse tumor livers, the expression pattern of which highly similar to that of forkhead Box M1 (FoxM1). Moreover, either knockdown of FoxM1 or site-directed mutagenesis of FoxM1-binding site of Prx II promoter significantly reduced Prx II levels in H-ras(G12V)-HCC cells, indicating FoxM1 as a direct transcription factor of Prx II in HCC. Interestingly, the null mutation of Prx II markedly decreased the number and size of tumors in H-ras(G12V)-Tg livers. Consistent with this, knockdown of Prx II in H-ras(G12V)-HCC cells reduced the expression of cyclin D1, cell proliferation, anchorage-independent growth and tumor formation in athymic nude mice, whereas overexpression of Prx II increased or aggravated the tumor phenotypes. Importantly, the expression of Prx II was correlated with that of FoxM1 in HCC patients. The activation of extracellular signal-related kinase (ERK) pathway and the expression of FoxM1 and cyclin D1 were highly dependent on Prx II in H-ras(G12V)-HCC cells and H-ras(G12V)-Tg livers. Prx II is FoxM1-dependently-expressed antioxidant in HCC and function as an enhancer of Ras(G12V) oncogenic potential in hepatic tumorigenesis through activation of ERK/FoxM1/cyclin D1 cascade.
Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.|National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon, Korea.
Y-H
YH
Park
Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.|National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon, Korea.
S-U
SU
Kim
Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
T-H
TH
Kwon
School of Medicine, Chungnam National University, Daejeon, Korea.
J-M
JM
Kim
Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea.
I-S
IS
Song
Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
H-J
HJ
Shin
Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
B-K
BK
Lee
School of Medicine, Wonkwang University, Iksan, Korea.
D-H
DH
Bang
Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
S-J
SJ
Lee
College of Natural Sciences, Kyungpook National University, Daegu, Korea.
D-S
DS
Lee
National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
K-T
KT
Chang
World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang, Korea.
B-Y
BY
Kim
Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon, Korea.
D-Y
DY
Yu
D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D010455:Peptides / Q000494:pharmacology; D054464:Peroxiredoxins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014183:Transplantation, Heterologous
D000072278:Forkhead Box Protein M1; D010455:Peptides; C024711:siomycin A; D054464:Peroxiredoxins; D016283:Proto-Oncogene Proteins p21(ras)