Thioredoxin 1 mediates TGF-β-induced epithelial-mesenchymal transition in salivary adenoid cystic carcinoma.
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.
Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, PR China.
Yang
Y
Jiang
Department of Otolaryngology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Xin
X
Feng
Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, PR China.
Lei
L
Zheng
Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, PR China.
Sheng-Lin
SL
Li
Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, PR China.
Xi-Yuan
XY
Ge
Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, PR China.
Jian-Guo
JG
Zhang
D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D003528:Carcinoma, Adenoid Cystic / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012468:Salivary Gland Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D054481:Thioredoxin Reductase 1 / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; C513384:CDH1 protein, human; C050361:CDH2 protein, human; D015820:Cadherins; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; C491203:TXN protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D013879:Thioredoxins; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
TGF-β; epithelial-mesenchymal transition; metastasis; salivary adenoid cystic carcinoma; thioredoxin 1