한빛사 논문
Abstract
1Cancer Research Institute, College of Medicine, Cell Dynamics Research Center, Seoul National University, Seoul 110-799, Korea
2Departments of Molecular & Clinical Oncology, Seoul National University, Seoul 110-799, Korea
3Division of Applied Life Science, Gyeongsang National University, Jinju 660-701, Korea
4Department of Medicine, Cheju National University, Jeju 690-756, Korea
5Departments of Tumor Biology, Seoul National University, Seoul 110-799, Korea
6Departments of Biomedical Sciences, Seoul National University, Seoul 110-799
*Correspondence to Ki Hun Park, Division of Applied Life Science, Gyeongsang National University, Jinju 660-701, Korea
*Correspondence to Jung Weon Lee, Cancer Research Institute, College of Medicine, Cell Dynamics Research Center, Seoul National University, Seoul 110-799, Korea
+Ph: 82-55-751-5472; Fax: 82-55-757-0178
++Ph: 82-2-3668-7030; Fax: 82-2-766-4487
Keywords
contact inhibition, epithelial-mesenchymal transition, TM4SF5, anti-tumorigenic reagent, liver carcinoma
We previously reported that the four-transmembrane L6 family member 5 (TM4SF5) was highly expressed in hepatocarcinoma, induced morphological elongation and epithelial-mesenchymal transition (EMT), and caused abnormal cell growth in multilayer in vitro and tumor formation in vivo (J. Clin. Invest. 2008;118:1354-1366). In this study, we identified a synthetic compound, 4''-(p-toluenesulfonylamido)-4-hydroxychalcone (TSAHC) that antagonized both the TM4SF5-mediated multilayer growth and -enhanced migration/invasion. TSAHC treatment induced multilayer-growing cells to grow in monolayer, recovering contact inhibition without accompanying apoptosis, and inhibited chemotactic migration and invasion. Tumor formation in nude mice injected with TM4SF5-expressing cells and the growth of cells expressing endogenous TM4SF5, but not of TM4SF5-null cells, was suppressed by treatment with TSAHC, but not by treatment with its analogues. The structure-activity relationship indicated the significance of 4''-p-toluenesulfonylamido and 4-hydroxy groups for the anti-TM4SF5 effects. Point mutations of the putative N-glycosylation sites abolished the TM4SF5-specific TSAHC responsiveness. Conclusion: These observations suggest that TM4SF5-enhanced tumorigenic proliferation and metastatic potential can be blocked by TSAHC, likely through targeting the extracellular region of TM4SF5, which is important for protein-protein interactions. (HEPATOLOGY 2008.)
Received: 3 July 2008; Revised: 7 November 2008; Accepted: 28 November 2008
Digital Object Identifier (DOI)
10.1002/hep.22777 About DOI
Additional Material
Additional Supporting Information may be found in the online version of this article.
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