Oncotarget

Research Papers:

TGF-β1 induces epigenetic silence of TIP30 to promote tumor metastasis in esophageal carcinoma

Fangfang Bu, Xing Liu, Jingjing Li, Shukun Chen, Xin Tong, Chunsheng Ma, Hui Mao, Fei Pan, Xiaoyan Li, Bo Chen, Liyan Xu, Enmin Li, Geng Kou, Jun Han, Shangjing Guo, Jian Zhao and Yajun Guo _

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Oncotarget. 2015; 6:2120-2133. https://doi.org/10.18632/oncotarget.2940

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Abstract

Fangfang Bu1,2,3,*, Xing Liu4,*, Jingjing Li1,*, Shukun Chen1, Xin Tong1,2,3, Chunsheng Ma4, Hui Mao1, Fei Pan1, Xiaoyan Li1,2, Bo Chen5, Liyan Xu5, Enmin Li5, Geng Kou1,2,6, Jun Han6, Shangjing Guo6, Jian Zhao1,2,3 and Yajun Guo1,2,3,6

1 PLA General Hospital Cancer Center Key Lab, Medical School of Chinese PLA, Beijing, P.R. China

2 International Joint Cancer Institute, The Second Military Medical University, Shanghai, P.R.China

3 Beijing Key Laboratory of Cell Engineering & Antibody, Beijing, P.R. China

4 The 150 Hospital of Chinese PLA, Luoyang, P.R.China

5 Department of Biochemistry and Molecular Biology & Institute of Oncologic Pathology, Shantou University Medical College, Shantou, P.R.China

6 Department of Pharmacy, Liaocheng University, Liaocheng, P.R. China

* These authors contributed equally to this work

Correspondence:

Yajun Guo, email:

Jian Zhao, email:

Keywords: TIP30, TGF-β1, methylation, epithelial-mesenchymal transition, ESCC

Received: October 22, 2014 Accepted: December 02, 2014 Published: December 03, 2014

Abstract

TGF-β1, 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-β1, an occurrence that was related to promoter hypermethylation. TGF-β1 induced TIP30 hypermethylation via increasing DNMT1 and DNMT3A expression, which could be restored by TGF-β 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-β1-induced EMT, and metastatic abilities of ESCC cells. Mechanically, TIP30 silencing induced the nuclear translocation and transcriptional activation of β-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 β-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-β1-induced activation of AKT/β-catenin signaling and ESCC metastasis.


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