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J. Biol. Chem., Vol. 282, Issue 47, 34594-34604, November 23, 2007

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Elevated Expression of Cyr61 Enhances Peritoneal Dissemination of Gastric Cancer Cells through Integrin ₂₁^*

Ming-Tsan Lin, Cheng-Chi Chang^¶, Been-Ren Lin^¶, Hsin-Yu Yang^¶, Chia-Yu Chu^¶||, Ming-Hsun Wu^¶, and Min-Liang Kuo^¶**1

From the Departments of Primary Care Medicine, Surgery, and ^||Dermatology, National Taiwan University Hospital, Taipei 100, the ^¶Laboratory of Molecular & Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei 100, and the ^**Angiogenesis Research Center, National Taiwan University, Taipei 100, Taiwan

Cysteine-rich 61 (Cyr61/CCN1) is involved in human gastric cancer development and progression. Nonetheless, the role of Cyr61 as regards peritoneal dissemination of such cancers has not yet been completely characterized. We used liposome-mediated transfection to establish Cyr61, or antisense Cyr61, expression vectors into gastric cancer AGS or MKN45 cell lines. Transfectants were tested by means of a cancer-cell adhesion assay in vitro and ex vivo. Furthermore, a functional integrin fluorescence-activated cell sorting assay, reverse transcription-PCR, and an AP-1 reporter assay were performed to investigate the potential signaling pathway of Cyr61. It was shown that stable transfection of Cyr61 into the AGS cell line strongly enhanced its adhesion ability. The overexpression of Cyr61 within AGS cells significantly increased the functional expression of integrin ₂₁. Function-neutralizing antibody to integrin ₂₁ effectively suppressed the Cyr61-mediated enhanced adhesion of AGS cells to peritoneal tissue. Promoter assays of integrin 2 gene further revealed that the AP-1 pathway was evidently activated within Cyr61-expressing AGS cells. Animal studies have revealed that mice injected with Cyr61-overexpressed AGS cells featured a greater number of peritoneal seeding nodules and a lower survival rate than the Neo control cell lines, and when such cells were treated with functional blocking antibody to integrin ₂₁, they were able to elicit a decline in the peritoneal dissemination. The data suggest that Cyr61 may contribute to the peritoneal dissemination of gastric cancer by promoting tumor-cell adhesion ability through the up-regulation of the functional integrin ₂₁ via an AP-1-dependent pathway.

Received for publication, August 9, 2007 , and in revised form, September 28, 2007.

^* This work was supported by grants from the National Science Council of Taiwan (Grants NSC94-2323-B-002-010, NSC94-2320-B-002-107, NSC-94-2320-B-002-012, and NSC95-2314-B-002-175) and the Department of Industrial Technology, Ministry of Economic Affairs, Taipei, Taiwan (Grant 92-EC-17-A-19-S1-0016). 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 should be addressed: Tel.: 886-2-2312-3456 (ext. 8607); Fax: 886-2-2341-0217; E-mail: toxkml{at}ha.mc.ntu.edu.tw.

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