Connective tissue growth factor is overexpressed in esophageal squamous cell carcinoma and promotes tumorigenicity through beta-catenin-T-cell factor/Lef signaling.
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 beta-catenin, leading to activation of beta-catenin-T-cell factor (TCF)/Lef signaling. Up-regulation of c-Myc and cyclin D1, two target genes of beta-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 beta-catenin or dominant negative TCF4. Furthermore, we identified a beta-catenin-TCF/Lef-binding site (TBE) in the promoter region of CTGF and found that CTGF is a transcriptional target of beta-catenin-TCF/Lef signaling. Taken together, these results revealed that the interaction of CTGF and beta-catenin-TCF/Lef forms a positive feedback loop, which could contribute to the tumorigenicity of ESCC.
Deng
Yue-Zhen
YZ
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Chen
Ping-Ping
PP
Wang
Yan
Y
Yin
Dong
D
Koeffler
H Phillip
HP
Li
Baojie
B
Tong
Xiang-Jun
XJ
Xie
Dong
D
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D056741:Cyclin D; D016213:Cyclins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051820:TCF Transcription Factors; D051176:beta Catenin; D055513:Connective Tissue Growth Factor