Epithin, a target of transforming growth factor-beta signaling, mediates epithelial-mesenchymal transition.
The epithelial-derived type II transmembrane serine protease epithin has been shown to be upregulated in a variety of cancer cell lines and tumor tissues, and its upregulation correlates well with tumor progression in many cases. However, little is known regarding the regulation of its expression and the mechanism of its roles in tumor progression. Here, we show that transforming growth factor-beta (TGF-beta), a potent inducer of epithelial-mesenchymal transition (EMT) in tumor progression, upregulates epithin, and that epithin plays a critical role in TGF-beta-induced EMT. Forced overexpression of epithin induced EMT to exhibit characteristic morphological changes, alternations in EMT-related proteins and enhanced cell motility. Conversely, shRNA-mediated knockdown of endogenous epithin inhibited TGF-beta-induced expression of mesenchymal markers and morphological changes. Furthermore, TGF-beta-induced cell migration and invasion were significantly impaired by epithin knockdown. In addition, we demonstrate that TGF-beta upregulates epithin transcriptionally via the Smad2/Smad4-mediated pathway. These results suggest that epithin is a key mediator of TGF-beta-induced EMT in tumor progression.
Lee
Hyo Seon
HS
School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
Kim
Chungho
C
Kim
Sang Bum
SB
Kim
Moon Gyo
MG
Park
Dongeun
D
D000818:Animals; D054338:Cell Transdifferentiation / Q000235:genetics*; D004285:Dogs; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D008565:Membrane Proteins; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051899:Smad2 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D012697:Serine Endopeptidases; C118992:St14 protein, mouse