PLoS ONE：硫氧还蛋白结合蛋白2增强TGF-β诱导的EMT

转化生长因子β（TGF-β）具有调节细胞生长、分化、凋亡、侵袭和各种癌症细胞的上皮间质转化（EMT）等关键作用。TGF-β诱导的EMT是癌细胞侵袭的重要一步。

硫氧还蛋白结合蛋白2 （TBP-2）在多种癌症类型中都表达下调，其表达不足的结果就是促发癌症患者的早期发病。不过，目前还不清楚TBP-2如何抑制癌症的侵袭和转移。PLoS ONE杂志上的一项研究中，科学家证明TBP-2的缺乏增加TGF-β的转录活性，也增强了TGF-β诱导Smad2磷酸化水平的功效。

敲除TBP-2能增强TGF-β调控Snail和Slug的表达，Snail和Slug是介导TGF-β诱导的EMT关键转录因子，TBP-2表达的降低能促进TGF-β诱导的A549细胞纺锤状形态的形成以及降低E-钙粘素的表达。

研究结果表明TBP-2缺失增强TGF-β的信号，促进TGF-β诱导的EMT。抑制TGF-β诱导的EMT对于侵袭和转移的抑制是至关重要的。因此，TBP-2是受TGF-β信号调控的一种新型分子，很可能是一个肿瘤预后指标，是肿瘤治疗的潜在靶标。

doi:10.1371/journal.pone.0039900
PMC:
PMID:

Deficiency of Thioredoxin Binding Protein-2 (TBP-2) Enhances TGF-β Signaling and Promotes Epithelial to Mesenchymal Transition

So Masaki1, Hiroshi Masutani1, Eiji Yoshihara1, Junji Yodoi1,2*

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.