Thymosin beta4 triggers an epithelial-mesenchymal transition in colorectal carcinoma by upregulating integrin-linked kinase.
The epithelial-mesenchymal transition (EMT) is crucial for the invasion and metastasis of many epithelial tumors including colorectal carcinoma (CRC). In the present study, a scattering and fibroblastic morphology with reduced intercellular contacts was found in the SW480 colon cancer cells overexpressing the gene encoding thymosin beta4 (Tbeta4), which was accompanied by a loss of E-cadherin as well as a cytosolic accumulation of beta-catenin, two most prominent markers of EMT. Whereas E-cadherin downregulation was likely to be accounted by a ZEB1-mediated transcriptional repression, the accumulation of beta-catenin was a result of glycogen synthase kinase-3beta inactivation mediated by integrin-linked kinase (ILK) and/or its downstream effector, Akt. Intriguingly, ILK upregulation in Tbeta4-overexpressing SW480 cells seemed to be attributed mainly to a stabilization of this kinase by complexing with particularly interesting new Cys-His protein (PINCH) more efficiently. In the meantime, a strong correlation between the expression levels of Tbeta4, ILK and E-cadherin in CRC patients was also revealed by immunohistochemical analysis. Taken together, these data suggest a novel role of Tbeta4 in promoting CRC progression by inducing an EMT in tumor cells via upregulating ILK and consequentially its signal transduction.
Huang
H-C
HC
Institute of Bioscience and Biotechnology, College of Life Science, National Taiwan Ocean University, Keelung, and Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.
Hu
C-H
CH
Tang
M-C
MC
Wang
W-S
WS
Chen
P-M
PM
Su
Y
Y
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D047389:Casein Kinase I / Q000378:metabolism; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000556:secondary; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016372:RNA, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013947:Thymosin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin / Q000378:metabolism; D000099201:Thymosin beta(4); D000099200:Scaffold Protein ILK
D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D047389:Casein Kinase I; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D016372:RNA, Antisense; D012333:RNA, Messenger; D013947:Thymosin; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin; D000099201:Thymosin beta(4); D000099200:Scaffold Protein ILK; C088088:LIMS1 protein, human; C486307:ZEB1 protein, human