Iron increases MMP-9 expression through activation of AP-1 via ERK/Akt pathway in human head and neck squamous carcinoma cells.
Head and neck squamous cell carcinoma (HNSCC) is a highly invasive cancer that is capable of distant metastasis and is a cause of great morbidity and mortality worldwide. Over-expression of matrix metalloproteinase-9 (MMP-9) is implicated in the invasion and metastasis of HNSCC. There is increasing evidence of an association between iron overload and cancer progression. However, the effect of iron on MMP-9 expression in HNSCC has not been studied. In the present study, we examined the effect of iron on MMP-9 expression in head and neck squamous carcinoma cell lines (OM-2 and HN-22). Ferric ammonium citrate (FAC), a source of iron, at 15 microg/ml increased MMP-9 in both cell lines in a dose-dependent manner as shown by reverse transcription polymerase chain reaction and gelatin zymography analyses. Studies using specific inhibitors of extracellular signal-regulated kinase (ERK1/2) and of Akt (SH-5) demonstrated that iron regulated MMP-9 through ERK1/2 and Akt, and that ERK1/2 was an upstream activator of Akt. Analysis of electrophoretic mobility shift assay revealed that iron induces MMP-9 expression by activation of activated protein-1 (AP-1). Application of neutralizing antibody against transferrin receptor could not abolish the stimulated MMP-9 expression, suggesting that iron uptake is non-transferrin dependent. In conclusion, this study is the first to demonstrate that MMP-9 was up-regulated by iron in HNSCC cell lines. We suggest that iron may be one of several factors that cause an increase of MMP-9, which is necessary for the development and progression of HNSCC.
Kaomongkolgit
Ruchadaporn
R
Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Henri-Dunant Road, Pathumwan, Bangkok, Thailand.
Cheepsunthorn
Poonlarp
P
Pavasant
Prasit
P
Sanchavanakit
Neeracha
N
D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D005290:Ferric Compounds / Q000494:pharmacology; D005786:Gene Expression Regulation; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D005290:Ferric Compounds; D000644:Quaternary Ammonium Compounds; D018808:Transcription Factor AP-1; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; C013531:ferric ammonium citrate