Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor-induced epithelial-mesenchymal transition

Zhi Chao Wang, Qiang Gao, Jie Yi Shi, Wei Jie Guo, Liu Xiao Yang, Xin Yang Liu, Long Zi Liu, Li Jie Ma, Meng Duan, Ying Jun Zhao, Yong Na Wu, Dong Mei Gao, Xiao Ying Wang, Guo Ming Shi, Zhen Bin Ding, Ai Wu Ke, Qi Qun Tang, Ya Cao, Jian Zhou, Jia Fan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1201-1214
Number of pages14
JournalHepatology
Volume62
Issue number4
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Fingerprint Dive into the research topics of 'Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor-induced epithelial-mesenchymal transition'. Together they form a unique fingerprint.

Cite this