Siah-1 is associated with expression of hypoxia-inducible factor-1α in oral squamous cell carcinoma.
OBJECTIVE
Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of the HIF-1α and HIF-1β subunits. HIF-1 is a central regulator of responses to hypoxia; it enhances metastasis-related factors such as matrix metalloproteinases and vascular endothelial growth factor (VEGF). We have reported critical roles for HIF-1α in tumor microenvironments, and oncogenic properties of HIF-1α have been suggested in malignancies. Seven in absentia homologue (Siah) appeared to upregulate HIF-1 production, which prompted us to investigate the Siah association with HIF-1α expression in oral squamous cell carcinoma (OSCC).


METHODS
Samples from fifty-five patients with OSCC were evaluated by immunohistochemistry for the protein expressions of Siah-1 and -2, HIF-1α, and VEGF. The expression levels of each protein and clinicopathological data were statistically analyzed.


RESULTS
Siah-1 and, Siah-2, HIF-1α, and VEGF were immunolocalized on the cell membranes and cytoplasm of the tumor cells. The expression of Siah-1 showed a linear dependence on the expression of HIF-1α (r=0.627, p<0.001). In 17 cases of the large tumor size category (T3 and 4), the mean Siah-1 expression score was significantly higher than in 41 cases of the small tumor size category (T1 and 2; p=0.001). In addition, in 16 cases of the lymph node metastasis-positive category (N1-3), the mean Siah-1 expression score was significantly higher than that in 42 cases of the lymph node metastasis-negative category (N0, p=0.001).


CONCLUSIONS
These results suggested that the expressions of Siah-1 and HIF-1α were clearly correlated in OSCC. Moreover, Siah-1 appears to be correlated with clinicopathological data, particularly tumor size.
Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
Mitsuharu
M
Aga
Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
Satoru
S
Kondo
Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
Naohiro
N
Wakisaka
Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
Makiko
M
Moriyama-Kita
Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
Kazuhira
K
Endo
Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
Yosuke
Y
Nakanishi
Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
Shigeyuki
S
Murono
Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
Hisashi
H
Sugimoto
Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
Takayoshi
T
Ueno
Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan. Electronic address: tomoy@med.kanazawa-u.ac.jp.
Tomokazu
T
Yoshizaki
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins
HIF-1α; Oral squamous cell carcinoma; Siah-1