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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Oncotarget 2015 ; 6 (4): 2120-33 Nephropedia Template TP
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TGF-?1 induces epigenetic silence of TIP30 to promote tumor metastasis in esophageal carcinoma #MMPMID25544767
Bu F; Liu X; Li J; Chen S; Tong X; Ma C; Mao H; Pan F; Li X; Chen B; Xu L; Li E; Kou G; Han J; Guo S; Zhao J; Guo Y
Oncotarget 2015[Feb]; 6 (4): 2120-33 PMID25544767show ga
TGF-?1, a potent EMT (epithelial-mesenchymal transition) inducer present in the tumor microenvironment, is involved in the metastasis and progression of various carcinomas, including esophageal squamous cell carcinoma (ESCC). TIP30 (30kDa HIV-1 Tat interacting protein) is a putative tumor metastasis suppressor. Here, we found TIP30 was decreased in cells undergoing EMT induced by TGF-?1, an occurrence that was related to promoter hypermethylation. TGF-?1 induced TIP30 hypermethylation via increasing DNMT1 and DNMT3A expression, which could be restored by TGF-? antibodies. In our in vitro and in vivo studies, we showed that silence of TIP30 led to EMT, enhanced migrative and invasive abilities of ESCC cells, promoted tumor metastasis in xenografted mice; alternatively, overexpression of TIP30inhibited TGF-?1-induced EMT, and metastatic abilities of ESCC cells. Mechanically, TIP30 silencing induced the nuclear translocation and transcriptional activation of ?-catenin in an AKT-dependent manner, which further resulted in the initiation of EMT. Consistently, TIP30 was frequently methylated and downregulated in ESCC patients. Loss of TIP30 correlated with nuclear ?-catenin and aberrant E-cadherin expression. TIP30 was a powerful marker in predicting the prognosis of ESCC. Taken together, our results suggest a novel and critical role of TIP30 involved in TGF-?1-induced activation of AKT/?-catenin signaling and ESCC metastasis.