Abstract

Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide, especially in China. However, the unclear pathogenesis of HCC necessitates in-depth investigation into underlying mechanisms for improving diagnosis and prognosis in China. In this study, the captured target sequencing of 497 Chinese HCC samples identified protein tyrosine phosphatase receptor type gamma ( PTPRG ) as a novel mutated gene with a higher frequency in Chinese patients than in foreign cohorts. Its expression was significantly down-regulated in tumors compared with adjacent normal tissues, and low expression correlated with poor prognosis. Gain- and loss-of-function assays confirmed that PTPRG acted as a tumor suppressor by inhibiting HCC growth, invasion, and metastasis both in vitro and in vivo . Mechanistically, PTPRG directly binds to the focal adhesion kinase (FAK), dephosphorylating FAK to inactivate PI3K/AKT signaling. The malignant phenotypes induced by PTPRG knockout were reversed by a FAK inhibitor, supporting FAK as a direct downstream target. Mutation of the D2 domain in PTPRG disrupted PTPRG–FAK binding and abrogated its tumor-suppressive effects. Additionally, CCAAT/enhancer-binding protein beta (CEBPB) was validated as a transcription factor activating PTPRG transcription, a finding corroborated by immunohistochemical staining showing a positive correlation in HCC tissues. To summarize, through our large-scale screening of Chinese HCC patients, PTPRG was identified as a novel, frequently mutated gene. Functional validation confirmed its tumor-suppressive role is compromised through two distinct mechanisms: post-translational suppression of FAK signaling via the D2 domain in mutant PTPRG and diminished transcriptional activation by CEBPB, resulting in reduced wild-type PTPRG expression, highlighting its potential as both a prognostic biomarker and a therapeutic