Abstract
Epithelial-to-mesenchymal transition (EMT) is well known to involve in tumor invasion and metastasis. Src homology region 2 domain-containing phosphatase 1 (SHP-1) functions as a potent tumor suppressor and also acts as a negative regulator of p-STAT3Tyr705 oncogenic signaling. However, little is known about the molecular mechanism(s) through which SHP-1 regulates EMT during hepatocellular carcinoma (HCC) progression. Here we first reported that endogenous SHP-1 protein levels were significantly downregulated in cells with mesenchymal characteristics and negatively correlated with p-STAT3Tyr705 and vimentin but positively correlated with E-cadherin. SHP-1 overexpression abolished transforming growth factor-β1 (TGF-β1)-induced p-STAT3Tyr705 and EMT, as well inhibited migration and invasion but further rescued by signal transducer and activator of transcription factor 3 (STAT3) overexpression. Depletion of SHP-1 could induce a more increase in TGF-β1-induced p-STAT3Tyr-705 and EMT characteristics, further supporting the mechanism that suppression of TGF-β1-induced EMT is dependent on SHP-1-mediated STAT3 inactivation. Constitutively overexpressed SHP-1 tyrosine phosphatase activity by D61A-mutated SHP-1 markedly reduced TGF-β1-induced p-STAT3Tyr705 and EMT features but was not altered by C453S catalytic-dead mutant SHP-1. Consequently, SHP-1 acted as a powerful suppressor in preventing EMT by exerting its tyrosine phosphatase activity that directly downregulated p-STAT3Tyr705. Most notably, we discovered a novel SHP-1 agonist SC-43 better than sorafenib to exert more potent anti-EMT effects in vitro as well as anti-metastatic growth in vivo. In conclusion, SHP-1 is a potent suppressor of HCC EMT and metastasis, thus highlighting that SC-43–SHP-1 axis may serve as a potential therapeutic target that antagonized p-STAT3Tyr705 and thereby prevented HCC EMT and metastasis.
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Acknowledgements
This work was supported by grants NSC 102-2325-B-002-031 and NHRI-EX102-10246BI from the National Science Council and the National Health Research Institutes, Taiwan. For SHP-1 and E-cadherin, gene expression levels were assessed by using microarray data deposited in the Gene Expression Omnibus (GEO) database under accession no. GSE25097.
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Fan, LC., Shiau, CW., Tai, WT. et al. SHP-1 is a negative regulator of epithelial–mesenchymal transition in hepatocellular carcinoma. Oncogene 34, 5252–5263 (2015). https://doi.org/10.1038/onc.2014.445
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DOI: https://doi.org/10.1038/onc.2014.445
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