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Thioredoxin 1 mediates TGF-β-induced epithelial-mesenchymal transition in salivary adenoid cystic carcinoma

2015; Impact Journals LLC; Volume: 6; Issue: 28 Linguagem: Inglês

10.18632/oncotarget.4635

1949-2553

Yang Jiang, Xin Feng, Lei Zheng, Shenglin Li, Xi‐Yuan Ge, Jianguo Zhang,

Cancer, Hypoxia, and Metabolism

// Yang Jiang 1 , Xin Feng 2 , Lei Zheng 1 , Sheng-Lin Li 3 , Xi-Yuan Ge 3 , Jian-Guo Zhang 1 1 Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, PR China 2 Department of Otolaryngology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA 3 Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, PR China Correspondence to: Jian-Guo Zhang, e-mail: rszhang@126.com Xi-Yuan Ge, e-mail: gexiyuan@bjmu.edu.cn Keywords: thioredoxin 1, epithelial-mesenchymal transition, metastasis, TGF-β, salivary adenoid cystic carcinoma Received: March 02, 2015 Accepted: August 07, 2015 Published: August 17, 2015 ABSTRACT Epithelial-mesenchymal transition (EMT) plays an important role in the invasion and metastasis of salivary adenoid cystic carcinoma (SACC) which is characterized by wide local infiltration, perineural spread, a propensity to local recurrence and late distant metastasis. Our recent studies have disclosed that TGF-β is a crucial factor for EMT in metastatic SACC. In this study, we further uncovered small redox protein thioredoxin 1 (TXN) as a critical mediator of TGF-β induced EMT. Immunohistochemistry analysis revealed significantly higher expressions of TXN, thioredoxin reductase 1 (TXNRD1) and N-cadherin, and lower expression of E-cadherin in human metastatic SACC compared to non-metastatic SACC tissues. Consistently, cultured SACC cells with stable TXN overexpression had decreased E-cadherin and increased N-cadherin as well as Snail and Slug expressions. The enhanced migration and invasion potential of these cells was abrogated by Akt or TXNRD1 inhibitors. Expression of N-cadherin and Akt p-Akt decreased, whereas E-cadherin expression increased in a BBSKE (TXNRD1 inhibitor)-dose-dependent manner. In a xenograft mouse model, TXN overexpression facilitated the metastatic potential of SACC-83 cells to the lung. Our results indicate that TXN plays a key role in SACC invasion and metastasis through the modulation of TGF-β-Akt/GSK-3β on EMT. TXN could be a potential therapeutic target for SACC.