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 TIP30 inhibited 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.
Highlights
Esophageal cancer, the eighth most common cancer in the world, is composed of two main histologic types: squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) [1]
We found that besides typical molecular changes of epithelial–mesenchymal transition (EMT), TIP30 expression was significantly decreased upon TGF-β1 treatment in esophageal squamous cell carcinoma (ESCC) cells
It was reported that Sorafenib, a tyrosine kinase inhibitor (TKI), decreased expression of TIP30 via JAK/STAT3 signaling in HCC [27]
Summary
Esophageal cancer, the eighth most common cancer in the world, is composed of two main histologic types: squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) [1]. The main risk factors for ESCC, the predominant type worldwide, include smoking and alcohol abuse, both inflammatory insults to the esophagus [2]. The molecular mechanisms underlying tumor metastasis in ESCC is poorly understood. Metastasis is a complex process involving acquires of motility and invasiveness properties and disseminates from primary tumors. TGF-β1, a potent EMT inducer present in the tumor microenvironment, is involved in the metastasis and progression of various carcinomas, including gastric [5], colorectal [6] and esophageal [7, 8] carcinoma. TGF-β1 induces EMT through multiple distinct signaling mechanisms [9]. The underlying mechanism of how TGF-β1 activates those pathways is still unclear
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