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