Iron increases HMOX1 and decreases hepatitis C viral expression in HCV-expressing cells.
OBJECTIVE
To investigate effects of iron on oxidative stress, heme oxygenase-1 (HMOX1) and hepatitis C viral (HCV) expression in human hepatoma cells stably expressing HCV proteins.


METHODS
Effects of iron on oxidative stress, HMOX1, and HCV expression were assessed in CON1 cells. Measurements included mRNA by quantitative reverse transcription-polymerase chain reaction, and protein levels by Western blots.


RESULTS
Iron, in the form of ferric nitrilotriacetate, increased oxidative stress and up-regulated HMOX1 gene expression. Iron did not affect mRNA or protein levels of Bach1, a repressor of HMOX1. Silencing the up-regulation of HMOX1 nuclear factor-erythroid 2-related factor 2 (Nrf2) by Nrf2-siRNA decreased FeNTA-mediated up-regulation of HMOX1 mRNA levels. These iron effects were completely blocked by deferoxamine (DFO). Iron also significantly decreased levels of HCV core mRNA and protein by 80%-90%, nonstructural 5A mRNA by 90% and protein by about 50% in the Con1 full length HCV replicon cells, whereas DFO increased them.


CONCLUSIONS
Excess iron up-regulates HMOX1 and down-regulates HCV gene expression in hepatoma cells. This probably mitigates liver injury caused by combined iron overload and HCV infection.
Cannon Research Center, Carolinas Medical Center, Charlotte, NC 28203, United States. herbert.bonkovsky@carolinashealthcare.org
Wei-Hong
WH
Hou
Lisa
L
Rossi
Ying
Y
Shan
Jian-Yu
JY
Zheng
Richard-W
RW
Lambrecht
Herbert-L
HL
Bonkovsky
D050976:Basic-Leucine Zipper Transcription Factors / Q000187:drug effects / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000494:pharmacology; D051856:Fanconi Anemia Complementation Group Proteins / Q000187:drug effects / Q000378:metabolism; D005290:Ferric Compounds / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D006526:Hepatitis C / Q000201:enzymology* / Q000235:genetics / Q000821:virology*; D006801:Humans; D007501:Iron / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000821:virology*; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D005290:Ferric Compounds; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014764:Viral Proteins; D007501:Iron; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D003676:Deferoxamine; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate