Glypican-3 (GPC3) is a cell-surface glycoprotein that is frequently overexpressed in hepatocellular carcinoma (HCC). GPC3 undergoes extensive posttranslational modification (PTM) including cleavage and glycosylation. This review focuses on the structure and function of GPC3 in liver cancer, highlighting the PTM of the tertiary and quaternary structures of GPC3 as a potential oncogenic regulatory mechanism. We propose that the function of GPC3 in normal development can vary with extensive PTM and that dysregulation of these processes leads to disease. Defining the regulatory impact of these modifications can provide a deeper understanding of the role of GPC3 in oncogenesis, epithelial–mesenchymal transition, and drug development. Through review of current literature, this article provides a unique perspective on the role of GPC3 in liver cancer, focusing on potential regulatory mechanisms of PTM on GPC3 function at the molecular, cellular, and disease level.

Introduction Glypican-3 (GPC3) is a surface-bound proteoglycan overexpressed in pediatric liver cancer and utilized clinically as an immunohistochemical tumor marker. Furin is a proprotein convertase that is ubiquitously expressed and shown to modify GPC3 post-translationally. In experimental models of epithelial-based cancers, furin inhibition decreased tumor cell migration and proliferation representing a potential therapeutic target. Methods Using a synthetic furin inhibitor, we evaluated proliferation, migration, protein, and RNA expression in two liver cancer cell lines, HepG2 (GPC3-positive) and SKHep1 cells (GPC3-negative). Total furin protein and GPC3 protein expression were assessed to evaluate functional levels of furin. Results There was a reduction in HepG2 proliferation with addition of furin inhibitor at the 48-h timepoint, however there was an increase in HepG2 migration. Conclusions GPC3 cleavage in hepatoblastoma (HB) has a role in cell proliferation with therapeutic potential, however furin inhibition is not an appropriate target for GPC3-expressing HB due to increased migration which may enhance metastatic potential.

Hepatoblastoma is the most common malignant liver tumor of childhood, with liver transplant and extended resection used as surgical treatments for locally advanced tumors. Although each approach has well-described post-operative complications, quality-of-life outcomes have not been described following the two interventions. Long-term pediatric survivors of hepatoblastoma who underwent conventional liver resection or liver transplantation at a single institution from January 2000–December 2013 were recruited to complete quality-of-life surveys. Survey responses for the Pediatric Quality of Life Generic Core 4.0 (PedsQL, n = 30 patient and n = 31 parent surveys) and Pediatric Quality of Life Cancer Module 3.0 (PedsQL-Cancer, n = 29 patient and n = 31 parent surveys) were collected from patients and parents. The mean total patient-reported PedsQL score was 73.7, and the parent-reported score was 73.9. There were no significant differences in scores on the PedsQL between patients who underwent resection compared to those who underwent transplantation (p > 0.05 for all comparisons). On the PedsQL-Cancer module, procedural anxiety scores were significantly lower for patients who underwent resection as compared to transplant (M = 33.47 points less, CI [−60.41, −6.53], p-value 0.017). This cross-sectional study demonstrates that quality of life outcomes are overall similar among patients receiving transplants and resections. Patients who received a resection reported worse procedural anxiety.

Relapse occurs in 10%–20% of children with hepatoblastoma and is associated with inferior outcomes, yet standardized management remains limited. Defining risk factors and relapse patterns, as well as the role of surgery, particularly transplantation, is critical to optimizing survival. A retrospective review was performed of patients aged 0–18 years diagnosed with hepatoblastoma from 2007 to 2024. Demographics, tumor characteristics, treatment course, relapse patterns, and outcomes were collected. Analyses included univariable and multivariable logistic regression, Kaplan–Meier survival estimation, and log‐rank testing. Among 135 patients, 98 (72.6%) achieved remission without relapse, 32 (23.7%) relapsed, and 5 (3.7%) experienced primary progression without remission. Older age, PRETEXT (pretreatment extent of disease) IV, metastatic disease at diagnosis, and macrovascular invasion were associated with relapse on univariable analysis, but only older age remained independently associated with relapse (adjusted odds ratio 1.27 per year, 95% confidence interval 1.05–1.53); PRETEXT IV and metastatic disease were not significantly associated with overall survival. Lung‐only relapse demonstrated favorable survival (100% alive), whereas combined liver and lung or extrahepatic relapse had poorer outcomes (40%–44% alive), although survival did not differ significantly across relapse sites ( p = 0.15). Of 54 liver transplant recipients, 44 underwent upfront transplantation, and 10 underwent salvage transplantation, with no significant difference in overall survival ( p = 0.90), although the salvage group was small. Relapse or progression after upfront transplantation occurred in 27% of recipients; lung‐only relapse again conferred favorable survival. Long‐term survival is achievable in relapsed hepatoblastoma, particularly for isolated pulmonary relapse. Older age, likely a surrogate for adverse tumor biology, was associated with relapse but did not preclude survival when aggressive multimodal therapy was used. Salvage transplantation achieved durable survival in selected patients and should be considered for unresectable intrahepatic relapse when extrahepatic disease is absent or controlled.