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

Oncogene volume 25, pages 3277–3285 (2006)Cite this article

Abstract

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.

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Acknowledgements

This work was supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan (15209024, 16590589).

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Y Uenoyama, H Seno, A Fukuda, A Sekikawa, A Nanakin, T Sawabu, M Kawada, N Kanda, K Suzuki, N Yada, H Fukui & T Chiba

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  1. Y Uenoyama
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  2. H Seno
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Correspondence to H Seno.

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Uenoyama, Y., Seno, H., Fukuda, A. et al. Hypoxia induced by benign intestinal epithelial cells is associated with cyclooxygenase-2 expression in stromal cells through AP-1-dependent pathway. Oncogene 25, 3277–3285 (2006). https://doi.org/10.1038/sj.onc.1209359

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