Abstract
BackgroundTransforming 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 FindingsIn 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/SignificanceOur 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.
Highlights
Transforming growth factor-b (TGF-b) has dual functions in cancer [1]
The results showed that transcriptional activity in response to Transforming growth factor beta (TGF-b) is enhanced in TBP-22/2 mouse embryonic fibroblasts (MEFs) compared with WT MEFs (Fig. 1A)
We demonstrated that deficiency of Thioredoxin binding protein-2 (TBP-2) increases TGF-b-responsive transcriptional activity and upregulates Smad2 phosphorylation levels, resulting in the acceleration of TGF-b-induced epithelial-mesenchymal transition (EMT)
Summary
Transforming growth factor-b (TGF-b) has dual functions in cancer [1]. TGF-b acts as a tumor suppressor in the early stage of tumor development, and contradictorily, promotes the invasion and metastasis of tumor cells in the late stage. Many studies have shown that TGF-b promotes cancer progression by inducing Epithelial-mesenchymal transition (EMT), which is a crucial process to acquire the ability to execute the invasionmetastasis steps of cancer [2,3]. Transforming growth factor beta (TGF-b) has critical roles in regulating cell growth, differentiation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) of various cancer cells. Thioredoxin binding protein-2 (TBP-2, called Txnip or VDUP1) is downregulated in various types of human cancer, and its deficiency results in the earlier onset of cancer. It remains unclear how TBP-2 suppresses the invasion and metastasis of cancer
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