Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer mortality globally. Understanding the molecular pathogenesis of HCC recurrence and metastasis is the key to improve patients' prognoses.
Immunohistochemical staining, quantitative PCR and western blots were used to detect the expression landscape of PTPN3 and multiple functional assays were conducted. Substrate-trapping mutant immunoprecipitation and antibodies microarrays were used to screen potential substrates. Promoter methylation status was also screened.
We found that protein tyrosine phosphatase N3 (PTPN3) was significantly downregulated in 78.6% of HCCs, and its expression negatively correlates with aggressive pathological features. In addition, PTPN3 deficiency is independently associated with shorter overall survival in patients. Restoration of PTPN3 expression significantly inhibits HCC cell migration and invasion in vitro as well as lung metastasis in vivo, and vice versa. Notably, PTPN3-regulated HCC invasiveness is accompanied by typical changes of epithelial-mesenchymal transition. Moreover, potential PTPN3 substrates were screened and we found that PTPN3 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 PTPN3, whereas silencing of EGFR re-inhibits metastasis caused by PTPN3 downregulation. Meanwhile, promoter hypermethylation of PTPN3 is frequently detected in HCC samples and cell lines.
These findings suggest that epigenetic inactivation of PTPN3 may increase the phosphorylation and activity of EGFR signaling to promote growth and metastasis in HCC.
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All authors have declared no conflicts of interest.