Acetaldehyde induces matrix metalloproteinase-9 gene expression via nuclear factor-kappaB and activator protein 1 signaling pathways in human hepatocellular carcinoma cells: Association with the invasive potential.
Alcohol consumption is a significant risk factor for hepatocellular carcinoma (HCC). Alcohol also increases the prevalence of invasion in HCC patients. However, the molecular mechanism on the metastatic effect of alcohol is unclear so far. Herein we demonstrated that acetaldehyde, the primary metabolite of ethanol, increased matrix metalloproteinase-9 (MMP-9) gelatinolytic activity and promoted cell invasion through the up-regulation of MMP-9 gene transcription in HepG2 cells. The transcription of MMP-9 gene was regulated by 10 microM acetaldehyde via inductions of nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) activities. Acetaldehyde stimulated the translocation of NF-kappaB into nucleus through inhibitory kappaB-alpha (IkappaB-alpha) and c-Jun N-terminal kinase (JNK)/beta-transducin repeat-containing protein (beta-TrCP) signaling pathways. Acetaldehyde also induced AP-1 activity via the phosphorylation of p38 kinase. In conclusion, our findings demonstrated for the first time that acetaldehyde activated NF-kappaB and AP-1 activities via IkappaB, JNK/beta-TrCP, and p38 signaling pathways, resulting in MMP-9 gene expression and hepatocarcinoma cells invasion. These results suggested that acetaldehyde might be a potential factor involved in the invasiveness of HCC in alcoholic patients.
Hsiang
Chien-Yun
CY
Department of Microbiology, China Medical University, Taichung 40402, Taiwan.
Wu
Shih-Lu
SL
Chen
Jaw-Chyun
JC
Lo
Hsin-Yi
HY
Li
Chia-Cheng
CC
Chiang
Su-Yin
SY
Wu
Hsiu-Ching
HC
Ho
Tin-Yun
TY
D000079:Acetaldehyde / Q000494:pharmacology*; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D000079:Acetaldehyde