Differential regulation of DEC2 among hypoxia-inducible genes in endometrial carcinomas.
In this study, we demonstrate an important role of activation of the hypoxia-inducible factor-1 (HIF-1) pathway in endometrial carcinogenesis and tumor phenotype development of endometrial carcinoma, and suggest a unique role of the HIF-1-target gene, differentiated embryo chondrocyte 2 (DEC2), in carcinogenesis. Hypoxia caused an increase in HIF-1alpha protein expression in 4 endometrial carcinoma cell lines. The expressions of its 5 target genes - DEC1, DEC2, carbonic anhydrase-9 (CA9), vascular endothelial growth factor (VEGF), and solute carrier family 2, member 1 (SLC2A1) - also reactively increased in most of the cell lines, except for DEC2 in the SNG-M cells. The expression levels of DEC2, CA9, and SLC2A1 were significantly higher in the 4 atypical hyperplasia tissues and 82 endometrial carcinomas compared with those in the 21 normal endometria. Clinicopathological analyses of carcinoma patients revealed a significant correlation of the VEGF and SLC2A1 expression with the status of lymph-vascular involvement and lymph node metastasis. The expression levels of CA9 and VEGF were significantly higher in the tumors of post- as opposed to pre-menopausal patients. The SLC2A1 expression was also related to the FIGO stage, but the DEC2 expression was inversely related to the FIGO grade. The activation of the HIF-1 pathway could be related to endometrial carcinogenesis, and the component, DEC2, could have different expression-regulatory mechanisms and unique roles in carcinogenesis.
Yunokawa
Mayu
M
Department of Translational Cancer Research, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
Tanimoto
Keiji
K
Nakamura
Hideaki
H
Nagai
Nobutaka
N
Kudo
Yoshiki
Y
Kawamoto
Takeshi
T
Kato
Yukio
Y
Hiyama
Eiso
E
Hiyama
Keiko
K
Nishiyama
Masahiko
M
D000951:Antigens, Neoplasm / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics*; D051272:Glucose Transporter Type 1 / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C422085:BHLHE41 protein, human; C403671:DELEC1 protein, human; C495677:SLC2A1 protein, human; C089226:CA9 protein, human