Hypoxia induced by benign intestinal epithelial cells is associated with cyclooxygenase-2 expression in stromal cells through AP-1-dependent pathway.
Cyclooxygenase-2 (COX-2) plays important roles in tumor development. Especially in the early-stage colorectal tumors, COX-2 expression is often observed in the tumor stroma. However, the mechanism regulating such stromal expression of COX-2 remains unknown. In the present study, we simulated the indirect interaction between epithelial cells and stromal cells in the process of colorectal tumor development using an in vitro co-culture model in which NIH3T3 fibroblasts were co-cultured with 'sparsely' or 'densely' populated intestinal epithelial cells, Intestine-407 as a model of premalignant or benign intestinal epithelial cells, and DLD-1 and Caco-2 as models of malignant epithelial cells. COX-2 expression in NIH3T3 fibroblasts was upregulated when co-cultured with the 'dense' epithelial cells regardless of their character. Interestingly, there was pericellular hypoxia in the vicinity of NIH3T3 fibroblasts when co-cultured with 'dense' epithelial cells, and the recovery of the partial pressure of oxygen level resulted in the reduction of enhanced COX-2 expression only in NIH3T3 fibroblasts co-cultured with 'dense' Intestine-407 cells. Furthermore, COX-2 expression was also reduced by the inhibition of transcription factor AP-1. Thus, pericellular hypoxia of the stromal cells caused by densely populated epithelial cells may be one of the potent COX-2 enhancers before completion of malignant transformation during intestinal tumor development.
Uenoyama
Y
Y
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Seno
H
H
Fukuda
A
A
Sekikawa
A
A
Nanakin
A
A
Sawabu
T
T
Kawada
M
M
Kanda
N
N
Suzuki
K
K
Yada
N
N
Fukui
H
H
Chiba
T
T
D000818:Animals; D018938:Caco-2 Cells; D002452:Cell Count; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000502:physiology; D004790:Enzyme Induction / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000201:enzymology* / Q000473:pathology; D007413:Intestinal Mucosa / Q000166:cytology* / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D041681:NIH 3T3 Cells; D011230:Precancerous Conditions / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000502:physiology*
D008565:Membrane Proteins; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human