Expression of ets-1 transcription factor in human head and neck squamous cell carcinoma and effect of histamine on metastatic potential of invasive tumor through the regulation of expression of ets-1 and matrix metalloproteinase-3.
BACKGROUND
Ets-1 controls the expression of critical genes involved in matrix remodeling. The matrix metalloproteinase-3 (MMP-3) and urokinase type plasminogen activator (uPA) are typical ets-1 responsive genes. Recent studies have shown an increase in histamine synthesis and content in various human neoplasias. We hypothesized that the increased local histamine overproduction contributed to activation of matrix remodeling through the activation of MMP-3 expression of peritumoral fibroblasts by means of ets-1 regulation in head and neck squamous cell carcinomas (HNSCCs).


METHODS
Paraffin-embedded sections of 30 HNSCCs were immunostained for ets-1. The presence of ets-1 and MMP-3 mRNA in tumor samples was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR). To simulate stromal reaction in vitro, cultured human mucosal fibroblast was used. The level of ets-1 and MMP-3 mRNA was compared by use of RT-PCR, as was their protein with flow-cytometry, in the presence or absence of basic fibroblast growth factor (bFGF) (10 ng/mL) and histamine (1 microM).


RESULTS
Correlation between ets-1 expression and clinicopathologic background was not significant. In all cases, expression of ets-1 was seen in the stroma. In in vitro study, histamine upregulates production of ets-1 and MMP-3 in cultured fibroblast, and bFGF can stimulate histamine expression in fibroblast. Immunofluorescence staining supported the results of RT-PCR and flow cytometry.


CONCLUSIONS
Ets-1 expression in HNSCCs has no prognostic value; however, ets-1 plays an important role in tumor-host interaction. Histamine may accelerate the spread of HNSCC through an ets-1-related mechanism.
Horváth
Barnabás
B
Department of Ear, Nose and Throat Diseases, National Medical Center 1135, Szabolcs u. 35, Budapest, Hungary. bhorvath@ogyik.hu
Hegyesi
Hargita
H
Nagy
Pál
P
Falus
András
A
Schaff
Zsuzsa
Z
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D018929:Cell Culture Techniques; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D014408:Biomarkers, Tumor; C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D016222:Fibroblast Growth Factor 2; D006632:Histamine; D019278:Matrix Metalloproteinase 3