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J. Biol. Chem., Vol. 283, Issue 23, 15807-15815, June 6, 2008

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Involvement of Hypoxia-inducing Factor-1-dependent Plasminogen Activator Inhibitor-1 Up-regulation in Cyr61/CCN1-induced Gastric Cancer Cell Invasion^*

Ming-Tsan Lin, I-Hsin Kuo^¶, Cheng-Chi Chang^¶, Chia-Yu Chu^¶||, Hsing-Yu Chen^¶, Been-Ren Lin^¶, Munisamy Sureshbabu^¶, Hou-Jung Shih^¶, and Min-Liang Kuo^¶**1

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

Cysteine-rich 61 (Cyr61/CCN1), one of the members of CCN family, has been implicated in the progression of human malignancies. Previously, our studies have demonstrated that Cyr61/CCN1 has a role in promoting gastric cancer cell invasion, but the mechanism is not clear yet. Here, we found that hypoxia-inducing factor-1 (HIF-1) protein, but not mRNA, expression was significantly elevated in gastric cancer cells overexpressing Cyr61. Supportively, a profound reduction of endogenous HIF-1 protein was noted in one highly invasive cell line, TSGH, when transfected with antisense Cyr61. By comparison, the induction kinetics of HIF-1 protein by recombinant Cyr61 (rCyr61) was distinct from that of insulin-like growth factor-1 and CoCl₂ treatment, both well known for induction of HIF-1. Using cycloheximide and MG132, we demonstrated that the Cyr61-mediated HIF-1 up-regulation was through de novo protein synthesis, rather than increased protein stability. rCyr61 could also activate the PI3K/AKT/mTOR and ERK1/2 signaling pathways, both of which were essential for HIF-1 protein accumulation. Blockage of HIF-1 activity in Cyr61-expressing cells by transfecting with a dominant negative (DN)-HIF-1 strongly inhibited their invasion ability, suggesting that elevation in HIF-1 protein is vital for Cyr61-mediated gastric cancer cell invasion. In addition, several HIF-1-regulated invasiveness genes were examined, and we found that only plasminogen activator inhibitor-1 (PAI-1) showed a significant increase in mRNA and protein levels in cells overexpressing Cyr61. Treatment with PAI-1-specific antisense oligonucleotides or function-neutralizing antibodies abolished the invasion ability of the Cyr61-overexpressing cells. Transfection with dominant negative-HIF-1 to block HIF-1 activity also effectively reduced the elevated PAI-1 level. In conclusion, our data provide a detailed mechanism by which Cyr61 promoted gastric cancer cell invasive ability via an HIF-1-dependent up-regulation of PAI-1.

Received for publication, October 30, 2007 , and in revised form, March 28, 2008.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and additional text.

¹ To whom correspondence should be addressed. Tel.: 886-2-2312-3456-8607; Fax: 886-2-2341-0217; E-mail: kuominliang{at}ntu.edu.tw.

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