title: Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor-induced epithelial-mesenchymal transition.
abstract: Hepatocellular carcinoma (HCC) is the third-most lethal cancer worldwide. Understanding the molecular pathogenesis of HCC recurrence and metastasis is the key to improve patients' prognosis. In this study, we report that protein tyrosine phosphatase receptor S (PTPRS) is significantly down-regulated in nearly 80% of HCCs, and its expression negatively correlates with aggressive pathological features, such as larger tumor size and advanced stage. In addition, PTPRS deficiency is independently associated with shorter survival and increased recurrence in patients, although 16.7% of HCCs show intratumor heterogeneous expression of PTPRS. Restoration of wild-type, but not mutant, PTPRS expression significantly inhibits HCC cell migration and invasion in vitro as well as lung metastasis in vivo, whereas knockdown of its expression significantly promotes invasion and metastasis. Notably, PTPRS-regulated HCC invasiveness is accompanied by typical changes of epithelial-mesenchymal transition (EMT). Moreover, PTPRS forms a complex with epithermal growth factor receptor (EGFR) and regulates its tyrosine residues' phosphorylation. Ectopic expression of EGFR reverses the metastasis-inhibiting effects of PTPRS, whereas silencing of EGFR or inhibiting phosphorylation of key molecules in EGFR downstream pathways reinhibits EMT and metastasis caused by PTPRS down-regulation. Meanwhile, promoter hypermethylation of PTPRS is frequently detected in HCC samples and cell lines. Treatment with a demethylation agent, 5-aza-2'-deoxycytidine, recovers PTPRS expression in a dose-dependent manner.
  
  
  CONCLUSIONS
  Epigenetic inactivation of PTPRS may increase phosphorylation and activity of EGFR signaling to promote EMT and metastasis in HCC.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Jie-Yi
authors.initials: JY
authors.lastname: Shi
authors.affiliation: Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Wei-Jie
authors.initials: WJ
authors.lastname: Guo
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Liu-Xiao
authors.initials: LX
authors.lastname: Yang
authors.affiliation: Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xin-Yang
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Long-Zi
authors.initials: LZ
authors.lastname: Liu
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Li-Jie
authors.initials: LJ
authors.lastname: Ma
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Duan
authors.affiliation: Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Ying-Jun
authors.initials: YJ
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, the First Hospital of Lanzhou University, Lanzhou, China.
authors.forename: Yong-Na
authors.initials: YN
authors.lastname: Wu
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Gao
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Guo-Ming
authors.initials: GM
authors.lastname: Shi
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Zhen-Bin
authors.initials: ZB
authors.lastname: Ding
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
authors.forename: Ai-Wu
authors.initials: AW
authors.lastname: Ke
authors.affiliation: Key Laboratory of Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.
authors.forename: Qi-Qun
authors.initials: QQ
authors.lastname: Tang
authors.affiliation: Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.|Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.|Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000556:secondary*; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D009362:Neoplasm Metastasis; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000502:physiology*; D017978:Receptors, Growth Factor; D014407:Tumor Cells, Cultured
chemical_list: D017978:Receptors, Growth Factor; D066246:ErbB Receptors; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2