title: Downregulation of thrombomodulin, a novel target of Snail, induces tumorigenesis through epithelial-mesenchymal transition.
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 with β-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-cadherin and 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.
authors: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Yuan-Chung
authors: YC
authors: Kao
authors: Li-Wha
authors: LW
authors: Wu
authors: Chung-Sheng
authors: CS
authors: Shi
authors: Che-Hsien
authors: CH
authors: Chu
authors: Chia-Wei
authors: CW
authors: Huang
authors: Chou-Pin
authors: CP
authors: Kuo
authors: Hamm-Ming
authors: HM
authors: Sheu
authors: Guey-Yueh
authors: GY
authors: Shi
authors: Hua-Lin
authors: HL
authors: Wu
mesh_terms: D000818:Animals; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D018180:Thrombomodulin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D015820:Cadherins; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D018180:Thrombomodulin; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D002118:Calcium