Clinicopathologic significance of hypoxia-inducible factor 1alpha overexpression in gastric carcinomas.
BACKGROUND
Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a key role in responses to hypoxia and expression of HIF-1alpha downstream genes leads to both an adapted metabolism and increased oxygen supply. We investigated the clinical significance of HIF-1alpha expression in gastric carcinoma.


METHODS
We examined HIF-1alpha, vascular endothelial growth factor (VEGF), and insulin-like growth factor-2 (IGF-2) expression patterns immunohistochemically in 126 specimens of gastric carcinoma. CD34 antigen levels were also examined by immunohistochemistry to determine microvessel density (MVD) within tumors and correlations between HIF-1alpha expression, clinicopathological features, and survival were examined.


RESULTS
HIF-1alpha expression correlated with tumor size (P<0.005), depth of invasion (P=0.018), VEGF expression (P=0.03), and intra-tumor MVD (P<0.005). IGF-2 expression was more prevalent in HIF-1alpha positive than in HIF-1alpha negative tumors and the 5-year survival rate was 58.4% for HIF-1alpha positive patients and 81.5% for HIF-1alpha negative patients (P=0.009). HIF-1alpha expression is an independent prognostic factor in gastric carcinoma (P=0.032).


CONCLUSIONS
Overexpression of HIF-1alpha in gastric carcinomas may upregulate its downstream gene products leading to VEGF-mediated angiogenesis, and resulting in a poor prognosis for patients.
Mizokami
Ken
K
Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, and Department of Pathology, Saga Prefectural Hospital Koseikan, Japan.
Kakeji
Yoshihiro
Y
Oda
Shinya
S
Irie
Koji
K
Yonemura
Tomohiro
T
Konishi
Fumio
F
Maehara
Yoshihiko
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005743:Gastrectomy; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000473:pathology; D011379:Prognosis; D013274:Stomach Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000502:physiology
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D007335:Insulin-Like Growth Factor II