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Natsuizaka M , Ohashi S , Wong GS , Ahmadi A , Kalman RA , Budo D , Klein-Szanto AJ , Herlyn M , Diehl JA , Nakagawa H
Insulin-like growth factor-binding protein-3 promotes transforming growth factor-beta 1-mediated epithelial-to-mesenchymal transition and motility in transformed human esophageal cells
Carcinogenesis. 2010 Aug;31(8) :1344-1353
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Insulin-like growth factor-binding protein (IGFBP)-3 is overexpressed frequently in esophageal squamous cell carcinoma. Yet, the role of IGFBP3 in esophageal tumor biology remains to be elucidated. We find that IGFBP3 facilitates transforming growth factor (TGF)-beta 1-mediated epithelial-to-mesenchymal transition (EMT) in transformed human esophageal epithelial cells, EPC2-hTERT-EGFR-p53(R175H). In organotypic 3D culture, a form of human tissue engineering, laser-capture microdissection revealed concurrent upregulation of TGF-beta target genes, IGFBP3 and EMT-related genes in the cells invading into the stromal compartment. IGFBP3 enhanced TGF-beta 1-mediated EMT as well as transcription factors essential in EMT by allowing persistent SMAD2 and SMAD3 phosphorylation. TGF-beta 1-mediated EMT and cell invasion were enhanced by ectopically expressed IGFBP3 and suppressed by RNA interference directed against IGFBP3. The IGFBP3 knockdown effect was rescued by IGFBP3(I56G/L80G/L81G), a mutant IGFBP3 lacking an insulin-like growth factor (IGF)-binding capacity. Thus, IGFBP3 can regulate TGF-beta 1-mediated EMT and cell invasion in an IGF or insulin-like growth factor 1 receptor-independent manner. IGFBP3(I56G/L80G/L81G) also promoted EMT in vivo in a Ras-transformed human esophageal cell line T-TeRas upon xenograft transplantation in nude mice. In aggregate, IGFBP3 may have a novel IGF-binding independent biological function in regulation of TGF-beta 1-mediated EMT and cell invasion.
Natsuizaka, Mitsuteru Ohashi, Shinya Wong, Gabrielle S. Ahmadi, Azal Kalman, Ross A. Budo, Daniela Klein-Szanto, Andres J. Herlyn, Meenhard Diehl, J. Alan Nakagawa, Hiroshi Oxford univ press Oxford 636bv