PTPRε Acts as a Metastatic Promoter in Hepatocellular Carcinoma by Facilitating Recruitment of SMAD3 to TGF‐β Receptor 1

Transforming growth factor beta (TGF-beta) suppresses early stages of tumorigenesis, but contributes to migration and metastasis of cancer cells. However, the role of TGF-beta signaling in invasive prometastatic hepatocellular carcinoma (HCC) is poorly understood. In this study, we investigated the roles of canonical TGF-beta/SMAD3 signaling and identified downstream effectors on HCC migration and metastasis. By using in vitro trans-well migration and invasion assays and in vivo metastasis models, we demonstrated that SMAD3 and Protein Tyrosine Phosphatase Receptor Epsilon (PTPRepsilon) promotes migration, invasion and metastasis of HCC cells in vitro and in vivo. Further mechanistic studies revealed that, upon TGF-beta stimulation, SMAD3 binds directly to PTPRepsilon promoters to activate its expression. PTPRepsilon interacts with TGFBR1/SMAD3 and facilitates recruitment of SMAD3 to TGFBR1, resulting a sustained SMAD3 activation status. The tyrosine phosphatase activity of PTPRepsilon is important for binding with TGFBR1, recruitment and activation of SMAD3, and its prometastatic role in vitro. A positive correlation between pSMAD3/SMAD3 and PTPRepsilon expression were determined in HCC samples, and high expression of SMAD3 or PTPRepsilon was associated with poor prognosis of HCC patients. Conclusion PTPRepsilon positively feedback regulates TGF-beta/SMAD3 signaling to promote HCC metastasis.