E1AF expression is closely correlated with malignant phenotype of tongue squamous cell carcinoma through activation of MT1-MMP gene promoters.
E1AF is an ets-oncogene family transcription factor that has been shown to up-regulate multiple MMPs whereas MMP-2, a potent extracellular matrix degrading enzyme, is not up-regulated. We investigated the activation mechanism of MMP-2 in oral squamous cell carcinoma. Chloramphenicol acetyltransferase (CAT) assay was utilized to investigate whether E1AF is able to up-regulate membrane type-1 matrix metalloproteinase (MT1-MMP), which is known to activate MMP-2. Expression of the CAT reporter gene under the control of the MT1-MMP promoter was increased approximately 40-fold by co-transfection with the E1AF expression vector. Real-time RT-PCR study was carried out in 25 patients with tongue squamous cell carcinoma, and the mRNA expression level of E1AF and MT1-MMP was synergistically increased. These results indicate that E1AF positively regulates transcription from MT1-MMP genes, which plays an important role in invasion and metastasis of squamous cell carcinoma of the tongue by converting pro-MMP-2 into active-MMP-2.
Izumiyama
Yuri
Y
Department of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, N13 W7, Kita-Ku, Sapporo 060-8586, Japan.
Ohiro
Yoichi
Y
Higashino
Fumihiro
F
Yoshida
Koichi
K
Taguchi
Kazunori
K
Todo
Satoru
S
Kohgo
Takao
T
Totsuka
Yasunori
Y
Shindoh
Masanobu
M
D017500:Adenovirus E1A Proteins / Q000096:biosynthesis*; D000328:Adult; D000368:Aged; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D050783:Proto-Oncogene Proteins c-ets; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014062:Tongue Neoplasms / Q000473:pathology*; D015854:Up-Regulation
D017500:Adenovirus E1A Proteins; D018076:DNA, Complementary; C079853:ETV4 protein, human; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D012313:RNA; D015500:Chloramphenicol O-Acetyltransferase; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases