10628

TXNIP

BACKGROUND: Transforming growth factor beta (TGF-beta) has critical roles in regulating cell growth, differentiation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) of various cancer cells. TGF-beta-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-beta and also enhances TGF-beta-induced Smad2 phosphorylation levels. Knockdown of TBP-2 augmented the TGF-beta-responsive expression of Snail and Slug, transcriptional factors related to TGF-beta-mediated induction of EMT, and promoted TGF-beta-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-beta signaling and promotes TGF-beta-induced EMT. The control of TGF-beta-induced EMT is critical for the inhibition of the invasion and metastasis. Thus TBP-2, as a novel regulatory molecule of TGF-beta signaling, is likely to be a prognostic indicator or a potential therapeutic target for preventing tumor progression.

epithelial to mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both high glucose and transforming growth factor-beta (TGF-beta) are able to induce EMT in cell culture. In this study, we examined the role of the thioredoxin-interacting protein (TXNIP) on EMT induced by high glucose or TGF-beta1 in HK-2 cells. EMT was assessed by the expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin and the induction of a myofibroblastic phenotype. High glucose (30mM) was shown to induce EMT at 72h. This was blocked by knockdown of TXNIP or antioxidant NAC. Meanwhile, we also found that knockdown of TXNIP or antioxidant NAC inhibited high glucose-induced generation of reactive oxygen species (ROS), phosphorylation of p38 MAPK and ERK1/2 and expression of TGF-beta1. HK-2 cells that were exposed to TGF-beta1 (4ng/ml) also underwent EMT. The expression of TXNIP gene and protein was increased in HK-2 cells treated with TGF-beta1. Transfection with TXNIP shRNA was able to attenuate TGF-beta1 induced-EMT. These results suggested that knockdown of TXNIP antagonized high glucose-induced EMT by inhibiting ROS production, activation of p38 MAPK and ERK1/2, and expression of TGF-beta1, highlighting TXNIP as a potential therapy target for diabetic nephropathy.CI - (c) 2013.

Malignant melanoma is highly lethal due to its aggressive invasive properties and metastatic dissemination. The transcription factor E2F1 is crucial for melanoma progression through poorly understood mechanisms. Here, we show that the miR-224/miR-452 cluster is significantly increased in advanced melanoma and invasive/metastatic cell lines that express high levels of E2F1. miR-224/miR-452 expression is directly activated by E2F1 through transactivation of the GABRE gene. Ectopic expression of miR-224/miR-452 in less aggressive cells induces EMT and cytoskeletal rearrangements and enhances migration/invasion. Conversely, miR-224/miR-452 depletion in metastatic cells induces the reversal of EMT, inhibition of motility, loss of the invasive phenotype and an absence of lung metastases in mice. We identify the metastasis suppressor TXNIP as new target of miR-224/miR-452 that induces feedback inhibition of E2F1 and show that miR-224/452-mediated downregulation of TXNIP is essential for E2F1-induced EMT and invasion. The E2F1-miR-224/452-TXNIP axis constitutes a molecular signature that predicts patient survival and may help to set novel therapies.CI - (c) 2014 The Authors.