High-level expression of the Smad ubiquitin ligase Smurf2 correlates with poor prognosis in patients with esophageal squamous cell carcinoma.
Transforming growth factor beta (TGF-beta) regulates growth of various cells, and inactivation of the TGF-beta signaling pathway contributes to tumor progression. Smad2 is phosphorylated and activated by TGF-beta, resulting in the antiproliferative effects of TGF-beta signaling. Smurf2 (Smad ubiquitination regulatory factor 2) was identified as the Smad ubiquitin ligase that induces the ubiquitination and degradation of Smad2. This study was undertaken to elucidate the relationships between Smurf2 expression and the clinicopathological characteristics of patients with esophageal squamous cell carcinoma (SCC) and the correlation between Smurf2 and Smad2 expression. Surgical specimens obtained from 80 patients with esophageal SCC were subjected to immunohistochemical staining. Our data indicated that high-level expression of Smurf2 correlated with depth of invasion, lymph node metastasis, and a poor survival rate. We also found an inverse correlation between the expression of Smurf2 and Smad2. Western blotting analysis of esophageal SCC-derived cell lines revealed similar inverse correlations. We demonstrated that high-level expression of Smurf2 appears to correlate with tumor development and poor prognosis in patients with esophageal SCC and that alteration of Smad2 expression in the TGF-beta signaling pathway may be induced by enhancement of Smad2 degradation mediated by high-level expression of Smurf2.
Fukuchi
Minoru
M
Department of Surgery I, Gunma University Faculty of Medicine, Maebashi 371-8511, Japan. mfukuchi@med.gunma-u.ac.jp
Fukai
Yasuyuki
Y
Masuda
Norihiro
N
Miyazaki
Tatsuya
T
Nakajima
Masanobu
M
Sohda
Makoto
M
Manda
Ryokuhei
R
Tsukada
Katsuhiko
K
Kato
Hiroyuki
H
Kuwano
Hiroyuki
H
D030201:Activin Receptors, Type I / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008025:Ligases / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis; D051899:Smad2 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases
D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; D015534:Trans-Activators; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D008025:Ligases