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

Abstract

BACKGROUND:

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.

PRINCIPAL FINDINGS:

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.

CONCLUSIONS/SIGNIFICANCE:

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.

• Authors: So Masaki, Hiroshi Masutani, Eiji Yoshihara, Junji Yodoi
• Journal: PloS one (PLoS One) Vol. 7 Issue 6 Pg. e39900 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22768160 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Carrier Proteins
• RNA, Messenger
• SNAI1 protein, human
• Smad2 Protein
• Smad2 protein, mouse
• Snai2 protein, mouse
• Snail Family Transcription Factors
• TXNIP protein, human
• Transcription Factors
• Transforming Growth Factor beta
• Txnip protein, mouse
• Thioredoxins

Topics

• Animals
• Cadherins (metabolism)
• Carrier Proteins (metabolism)
• Cell Shape (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Gene Expression Regulation (drug effects)
• Gene Knockdown Techniques
• Humans
• Mice
• Phosphorylation (drug effects)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• Smad2 Protein (metabolism)
• Snail Family Transcription Factors
• Thioredoxins (metabolism)
• Transcription Factors (metabolism)
• Transcription, Genetic (drug effects)
• Transforming Growth Factor beta (metabolism, pharmacology)