Abstract
Abstract Epithelial-to-mesenchymal transition (EMT) is well known to involve in tumor invasion and metastasis. SH2 domain-containing phosphatase 1 (SHP-1) functions as a potent tumor suppressor and also acts as a negative regulator of p-STAT3 (Tyr705) oncogenic signaling. However, little is known about the molecular mechanism(s) through which SHP-1 regulates EMT during hepatocellular carcinoma (HCC) progression. Here, we firstly reported that endogenous SHP-1 protein levels were significantly down-regulated in cells with mesenchymal characteristics and negatively correlated with p-STAT3 (Tyr705) and vimentin but positively correlated with E-cadherin. SHP-1 overexpression abolished TGF-beta-induced p-STAT3 (Tyr705) and EMT, as well inhibited migration and invasion but further rescued by STAT3 overexpression. Constitutively overexpressed SHP-1 tyrosine phosphatase activity by D61A mutated SHP-1 markedly reduced TGF-beta-induced p-STAT3 (Tyr705) and EMT features, but not altered by C453S catalytic dead mutant SHP-1. Consequently, SHP-1 acted as a powerful suppressor in preventing EMT by exerting its activity directly targeted p-STAT3 (Tyr705). 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 anti-metastatic growth in vivo. In conclusion, SHP-1 is a potent suppressor of HCC EMT and metastasis, thus, highlighting that SHP-1 may serve as a potential therapeutic target for HCC EMT and metastasis. Note: This abstract was not presented at the conference. Citation Format: Li-Ching Fan, Chung-Wai Shiau, Wei-Tien Tai, Man-Hsin Hung, Pei-Yi Chu, Hang Lin, Hui-Chuan Yu, Kuen-Feng Chen. SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-01.
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