Downregulation of thrombomodulin, a novel target of snail, induces tumorigenesis through epithelial-mesenchymal transition

Yuan Chung Kao, Li Wha Wu, Chung Sheng Shi, Che Hsien Chu, Chia Wei Huang, Chou Pin Kuo, Hamm Ming Sheu, Guey Yueh Shi, Hua Lin Wu

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The expression of thrombomodulin (TM), a calcium-dependent adhesion molecule, is frequently downregulated in various cancer types. However, the mechanism responsible for the low expression level of TM in tumorigenesis is unknown. Here, an inverse expression of TM and Snail was detected in different cancer cell lines. We further confirmed this inverse relation using the epithelial-mesenchymal transition cell model in HaCaT and A431 cells. We demonstrated that Snail suppressed TM expression by binding to E-box (CACCTG) in TM promoter. Moreover, TM knockdown by short hairpin RNA disrupted E-cadherin-mediated cell junctions and contributed to tumorigenesis. In the calcium switch assay, E-cadherin lost the ability to associate withβ-catenin and accumulated in cytoplasm in TM knockdown cells. Meanwhile, wound healing and invasive assays showed that TM knockdown promoted cell motility. A subcutaneous injection of TM knockdown transfectants into immunocompromised mice induced squamous cell carcinoma-like tumors. Besides, forced expression of murine TM in TM knockdown cells made the cells reassume epithelium-like morphology and increased calcium-dependent association of E-cadherinand β-catenin. In conclusion, TM, a novel downstream target of Snail in epithelial-mesenchymal transition, is required for maintaining epithelial morphology and functions as a tumor suppressor.

Original languageEnglish
Pages (from-to)4767-4785
Number of pages19
JournalMolecular and Cellular Biology
Volume30
Issue number20
DOIs
Publication statusPublished - 2010 Oct

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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