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J. Biol. Chem., Vol. 282, Issue 50, 36571-36581, December 14, 2007

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Connective Tissue Growth Factor Is Overexpressed in Esophageal Squamous Cell Carcinoma and Promotes Tumorigenicity through β-Catenin-T-cell Factor/Lef Signaling^*

Yue-Zhen Deng, Ping-Ping Chen^¶, Yan Wang, Dong Yin, H. Phillip Koeffler^||, Baojie Li^**, Xiang-Jun Tong, and Dong Xie¹

From the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China, ^¶College of Public Health, Zhengzhou University, Zhengzhou 450052, China, ^||Division of Hematology/Oncology, School of Medicine, UCLA, Los Angeles, California 90048, ^**Institute of Molecular and Cell Biology, Singapore 138673, Singapore, and College of Life Sciences, Beijing University, Beijing 100083, China

Connective tissue growth factor (CTGF or CCN2), a member of the CCN family, is involved in diverse biological processes such as cell adhesion, proliferation, and angiogenesis. In this study, we show that overexpression of CTGF occurred in a significant proportion of esophageal squamous cell carcinoma (ESCC) samples that were of a high tumor grade and metastatic. Forced expression of CTGF in Eca109 ESCC cells accelerated their growth in culture and significantly increased tumor formation in nude mice, whereas RNA interference-mediated knockdown of CTGF in ESCC cells significantly inhibited cell growth and colony formation, as well as tumorigenicity in vivo. Moreover, overexpression of CTGF in ESCC cells resulted in the accumulation and nuclear translocation of β-catenin, leading to activation of β-catenin-T-cell factor (TCF)/Lef signaling. Up-regulation of c-Myc and cyclin D1, two target genes of β-catenin-TCF/Lef signaling, was also observed in the CTGF-overexpressing cells. These effects of CTGF in ESCC cells were abolished by transfection with either dominant negative β-catenin or dominant negative TCF4. Furthermore, we identified a β-catenin-TCF/Lef-binding site (TBE) in the promoter region of CTGF and found that CTGF is a transcriptional target of β-catenin-TCF/Lef signaling. Taken together, these results revealed that the interaction of CTGF and β-catenin-TCF/Lef forms a positive feedback loop, which could contribute to the tumorigenicity of ESCC.

Received for publication, May 21, 2007 , and in revised form, October 16, 2007.

^* This work was supported by 973 Program 2007CB914704, 863 Program 2007AA02Z474, National Natural Science Funds for Distinguished Young Scholar Grant 30725010, National Natural Science Foundation of China Grants 30470847 and 30528003, Chinese Academy of Sciences Grant KSCX-YW-R-73, Shanghai Pujang Program 06PJ14108, Science and Technology Commission of Shanghai Municipality Grants 04DZ14007 and 05DJ14009 (to D. X.), China Postdoctoral Science Foundation, Shanghai Postdoctoral Scientific Program, and Chinese Academy of Sciences K.C. Wong post-doctoral fellowships (to Y. W.). 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: Laboratory of Molecular Oncology, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Tai-Yuan Rd., Shanghai 200031, China. Tel.: 86-021-5492-0918; Fax: 86-021-5492-0291; E-mail: dxie{at}sibs.ac.cn.

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