Hypoxia induced by benign intestinal epithelial cells is associated with cyclooxygenase-2 expression in stromal cells through AP-1-dependent pathway

• Published in: Oncogene Vol. 25; no. 23; pp. 3277 - 3285
• Main Authors: UENOYAMA, Y, SENO, H, FUKUI, H, CHIBA, T, FUKUDA, A, SEKIKAWA, A, NANAKIN, A, SAWABU, T, KAWADA, M, KANDA, N, SUZUKI, K, YADA, N
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 01.06.2006; Nature Publishing Group
• Subjects: Activator protein 1; Animals; Biological and medical sciences; Caco-2 Cells; Cell Count; Cell culture; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Coculture Techniques; Colorectal cancer; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - physiology; Cyclooxygenase-2; Enhancers; Enzyme Induction - physiology; Epithelial cells; Fibroblasts; Fundamental and applied biological sciences. Psychology; Gene expression; Humans; Hypoxia; Hypoxia - enzymology; Hypoxia - pathology; Intestinal Mucosa - cytology; Intestinal Mucosa - enzymology; Intestinal Mucosa - pathology; Intestine; Membrane Proteins - biosynthesis; Membrane Proteins - physiology; Mice; Molecular and cellular biology; NIH 3T3 Cells; Oncology; Precancerous Conditions - enzymology; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Proteins; Signal transduction; Signal Transduction - physiology; Stromal cells; Stromal Cells - enzymology; Stromal Cells - pathology; Transcription Factor AP-1 - physiology; Transcription factors; Tumors; Oxygen; Enzyme; Cyclooxygenase 2; Gene expression; Carcinogenesis; Density; cell density; Epithelial cell; Hypoxia; Tumor; Oxidoreductases; Stromal cell; Fibroblast; colorectal tumor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209359

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.