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J. Biol. Chem., Vol. 283, Issue 21, 14335-14344, May 23, 2008

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Hyaluronan Constitutively Regulates Activation of COX-2-mediated Cell Survival Activity in Intestinal Epithelial and Colon Carcinoma Cells^*

Suniti Misra¹, Lina M. Obeid, Yusuf A. Hannun^¶, Susumu Minamisawa^||, Franklin G. Berger^**, Roger R. Markwald, Bryan P. Toole, and Shibnath Ghatak²

From the Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina 29425, Division of General Internal Medicine, Ralph H. Johnson Veterans Affairs Hospital, Charleston, South Carolina 29401, the ^¶Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, the ^||Department of Physiology, Yokohama City University, Yokohama 236-0004, Japan, and the ^**Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208

Hyaluronan is a major component of the pericellular matrix surrounding tumor cells, including colon carcinomas. Elevated cycooxygenase-2 levels have been implicated in several malignant properties of colon cancer. We now show for the first time a strong link between hyaluronan-CD44 interaction and cyclooxygenase-2 in colon cancer cells. First, we have shown that increased expression of hyaluronan synthase-2 induces malignant cell properties, including increased proliferation, anchorage-independent growth, and epithelial-mesenchymal transition in HIEC6 cells. Second, constitutive hyaluronan-CD44 interaction stimulates a signaling pathway involving ErbB2, phosphoinositide 3-kinase/AKT, β-catenin, and cyclooxygenase-2/prostaglandin E₂ in HCA7 colon carcinoma cells. Third, the HA/CD44-activated ErbB2 phosphoinositide 3-kinase/AKT β-catenin pathway stimulates cell survival/cell proliferation through COX-2 induction in hyaluronan-overexpressing HIEC6 cells and in HCA7 cells. Fourth, perturbation of hyaluronan-CD44 interaction by hyaluronan oligomers or CD44-silencing RNA decreases cyclooxygenase-2 expression and enzyme activity, and inhibition of cyclooxygenase-2 decreases hyaluronan production suggesting the possibility of an amplifying positive feedback loop between hyaluronan and cyclooxygenase-2. We conclude that hyaluronan is an important endogenous regulator of colon cancer cell survival properties and that cyclooxygenase-2 is a major mediator of these hyaluronan-induced effects. Defining hyaluronan-dependent cyclooxygenase-2/prostaglandin E₂-associated signaling pathways will provide a platform for developing novel therapeutic approaches for colon cancer.

Received for publication, May 9, 2007 , and in revised form, December 21, 2007.

^* This work was supported, in whole or in part, by National Institutes of Health Grants P20 RR017698 (to S. M. and F. D. B.), P20 RR016434 (to S. M., S. G., and R. R. M.), R01-CA87584 (to Y. A. H.), CA073839, and CA082867, and NIGMS Grant GM062887 (to L. M. O.). This work was also supported by Hollings Cancer Center Department of Defense Grant GC-3319-05-44598 (to S. M.), and MUSC URC Projects 2204000-24330 (to S. M.) and 2204000-24329 (to S. G.), and a Charlotte Geyer Foundation Award (to B. P. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Dept. of Cell Biology and Anatomy, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425. Tel.: 843-792-8642; Fax: 843-792-0664; E-mail: misra{at}musc.edu. ² To whom correspondence may be addressed. Tel.: 843-792-8642; Fax: 843-792-0664; E-mail: ghatak{at}musc.edu.

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