Hepatocellular carcinoma (HCC) stands as the third-most lethal cancer globally, with its recurrence and metastasis being critical issues that impact patient prognosis. Our study reveals that protein tyrosine phosphatase receptor S (PTPRS) is significantly down-regulated in nearly 80% of HCC cases. This down-regulation is inversely correlated with aggressive pathological features such as larger tumor size and advanced stage. Notably, PTPRS deficiency is independently linked to shorter survival and increased recurrence in patients, although 16.7% of HCCs display intratumoral heterogeneous expression of PTPRS.

Reintroducing wild-type PTPRS, as opposed to its mutant form, markedly inhibits HCC cell migration and invasion in vitro and reduces lung metastasis in vivo. Conversely, reducing PTPRS expression significantly promotes invasion and metastasis. The regulation of HCC invasiveness by PTPRS is associated with characteristic changes in epithelial-mesenchymal transition (EMT).

Furthermore, PTPRS forms a complex with the epidermal growth factor receptor (EGFR) and modulates the phosphorylation of its tyrosine residues. Overexpression of EGFR counteracts the metastasis-inhibiting effects of PTPRS, while silencing EGFR or inhibiting phosphorylation of downstream EGFR pathways reinstates EMT and metastasis inhibited by PTPRS down-regulation. Promoter hypermethylation of PTPRS is frequently observed in HCC samples and cell lines, and treatment with the demethylation agent 5-aza-2'-deoxycytidine restores PTPRS expression in a dose-dependent manner.

In summary, the epigenetic inactivation of PTPRS may elevate phosphorylation and activity of EGFR signaling, thereby promoting EMT and metastasis in HCC.

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