Deficiency of thioredoxin binding protein-2 (TBP-2) enhances TGF-β signaling and promotes epithelial to mesenchymal transition

• Published in: PloS one 2012-06, Vol.7 (6), p.e39900
• Main Authors: Masaki, So, Masutani, Hiroshi, Yoshihara, Eiji, Yodoi, Junji
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Binding; Biology; Bladder; Cadherins - metabolism; Cancer; Carrier Proteins - metabolism; Cell cycle; Cell growth; Cell Shape - drug effects; E-cadherin; Epithelial-Mesenchymal Transition - drug effects; Gene Expression Regulation - drug effects; Gene Knockdown Techniques; Humans; Infections; Kinases; Laboratories; Liver cancer; Medicine; Mesenchyme; Metastases; Metastasis; Mice; Phosphorylation; Phosphorylation - drug effects; Prevention; Protein deficiency; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; Smad2 protein; Smad2 Protein - metabolism; Snail Family Transcription Factors; Snail protein; Thioredoxin; Thioredoxins - metabolism; Toxicology; Transcription factors; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology; Transforming growth factor-b
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039900

Transforming growth factor beta (TGF-β) has critical roles in regulating cell growth, differentiation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) of various cancer cells. TGF-β-induced EMT is an important step during carcinoma progression to invasion state. Thioredoxin binding protein-2 (TBP-2, also called Txnip or VDUP1) is downregulated in various types of human cancer, and its deficiency results in the earlier onset of cancer. However, it remains unclear how TBP-2 suppresses the invasion and metastasis of cancer. In this study, we demonstrated that TBP-2 deficiency increases the transcriptional activity in response to TGF-β and also enhances TGF-β-induced Smad2 phosphorylation levels. Knockdown of TBP-2 augmented the TGF-β-responsive expression of Snail and Slug, transcriptional factors related to TGF-β-mediated induction of EMT, and promoted TGF-β-induced spindle-like morphology consistent with the depletion of E-Cadherin in A549 cells. Our results indicate that TBP-2 deficiency enhances TGF-β signaling and promotes TGF-β-induced EMT. The control of TGF-β-induced EMT is critical for the inhibition of the invasion and metastasis. Thus TBP-2, as a novel regulatory molecule of TGF-β signaling, is likely to be a prognostic indicator or a potential therapeutic target for preventing tumor progression.