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Increased Expression of CYR61, an Extracellular Matrix Signaling Protein, in Human Benign Prostatic Hyperplasia and Its Regulation by Lysophosphatidic Acid

Pharmaceutical Frontier Research Laboratories, JT Inc. (S.S., M.Y., K.N., T.H.), Yokohama City 236-0004, Japan; Department of Urology (X.Z., Y.K.), Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; Gene Logic Inc. (K.P.), Gaithersburg, Maryland 20878; and Department of Urology Research Laboratories (R.H.G.), University of Pittsburgh, Pittsburgh, Pennsylvania 15232

Address all correspondence and requests for reprints to: Shinji Sakamoto, Ph.D., Pharmaceutical Frontier Research Laboratories, JT Inc., 13-2, Fukuura 1-chome, Kanazawa-ku, Yokohama 236-0004, Japan. E-mail: shinji.sakamoto{at}ims.jti.co.jp.

Lysophosphatidic acid (LPA) is an endogenous lipid growth factor that is thought to play important roles in cell proliferation and antiapoptosis and therefore may have roles in the development and progression of benign prostatic hyperplasia (BPH). CYR61 (CCN1), on the other hand, is a growth factor-inducible immediate early gene that functions in cell proliferation, differentiation, and extracellular matrix synthesis. Here we show the close relationship between LPA-induced expression of CYR61 and prostate enlargement. CYR61 mRNA and protein were dramatically up-regulated by 18:1 LPA (oleoyl-LPA) within 1 and 2 h, respectively, in both stromal and epithelial prostatic cells. G protein-coupled receptors, i.e. Edg-2, Edg-4, and Edg-7, for LPA were also expressed in both stromal and epithelial prostatic cells. Furthermore, on DNA microarray analysis for normal and BPH patients, CYR61 was found to be related to the development and progression of BPH, regardless of symptoms. Although CYR61 mRNA was synthesized in hyperplastic epithelial cells, in many cases of BPH, CYR61 protein was detected in both the epithelial and stromal regions of BPH patient tissues. The functional contribution of CYR61 to prostatic cell growth was demonstrated by recombinant CYR61 protein and anti-CYR61 neutralizing antibodies, which inhibited CYR61-dependent cell spreading and significantly diminished cell proliferation, respectively. In conclusion, these data support the hypothesis that LPAs induce the expression of CYR61 by activating G proteincoupled receptors and that CYR61 acts as a secreted autocrine and/or paracrine mediator in stromal and epithelial hyperplasia, demonstrating the potential importance of this signaling mechanism in the disease.

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