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Updated: May 24, 2026
Non-Invasive PET/MR Imaging in an Orthotopic Mouse Model of Hepatocellular Carcinoma
Published on: August 31, 2022
Human hepatocellular carcinoma in a mouse model: assessment of tumor response to percutaneous ablation by using
Shanmugasundaram Ganapathy-Kanniappan1, Rani Kunjithapatham, Michael S Torbenson
1Russell H Morgan Department of Radiology and Radiological Sciences and Department of Pathology, Johns Hopkins University School of Medicine, 600 N Wolfe St, Blalock 545, Baltimore, MD 21287, USA.
Purpose:
To characterize tumor response to percutaneous injection of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) antagonists in a mouse model of human hepatocellular carcinoma (HCC).
Materials And Methods:
Animal experiments were approved by the Johns Hopkins University Animal Care and Use Committee. Luciferase (luc) gene-expressing Hep3B tumor-bearing athymic nude mice were randomly divided into four groups of six mice each. Tumor-specific GAPDH inhibition was achieved by using percutaneous injection of GAPDH antagonists-3-bromopyruvate (3-BrPA) or GAPDH-specific short hairpin RNA (shRNA). Tumor response to treatment was assessed by using bioluminescence imaging and analysis of GAPDH function and apoptotic markers (caspase-3, caspase-9, and positive staining for terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphospate nick end labeling). HCC samples from 34 patients were obtained from the Johns Hopkins tumor bank, as approved by the Institutional Review Board, for GAPDH expression analysis. Statistical analysis was performed by using a two-sample t test or Spearman rank correlation coefficient.
Results:
In vitro, 3-BrPA affected Hep3B cell viability (half maximal inhibitory concentration = 0.15 mmol/L), and GAPDH shRNA suppressed (45.5%) colony formation. In vivo, percutaneous injection of GAPDH antagonists into luc-Hep3B tumors decreased bioluminescence imaging signal and viability (3-BrPA, P < .0001; GAPDH shRNA, P = .03). The 3-BrPA treatment primarily inhibited GAPDH activity (74.5%) compared with its expression (34.3%), whereas GAPDH shRNA inhibited both activity (60.6%) and expression (44.4%). Targeted inhibition of GAPDH by using 3-BrPA or shRNA induced apoptosis. HCC samples from patients demonstrated a strong correlation between GAPDH upregulation and the proto-oncogene c-jun expression (r = 0.543, P = .003).
Conclusion:
Percutaneous injection of GAPDH antagonists induces apoptosis and blocks Hep3B tumor progression, which demonstrates the therapeutic potential of targeting GAPDH in human HCC.
Insights
Targeting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) with antagonists like 3-bromopyruvate or shRNA effectively reduced hepatocellular carcinoma (HCC) tumor growth in mice. This approach induced apoptosis and shows promise for treating human HCC.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) is a significant global health concern.
- Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is implicated in cancer progression.
- Targeting key enzymes like GAPDH presents a potential therapeutic strategy for HCC.
Purpose of the Study:
- To evaluate the efficacy of percutaneous injection of GAPDH antagonists in a mouse model of human HCC.
- To characterize tumor response, including apoptosis and enzyme activity, following GAPDH inhibition.
Main Methods:
- Athymic nude mice bearing luciferase-expressing Hep3B HCC tumors were treated with 3-bromopyruvate (3-BrPA) or GAPDH-specific short hairpin RNA (shRNA).
- Tumor response was assessed using bioluminescence imaging and analysis of GAPDH function and apoptotic markers.
- Human HCC samples were analyzed for GAPDH and c-jun expression.
Main Results:
- Both 3-BrPA and GAPDH shRNA significantly reduced tumor viability and bioluminescence in vivo.
- 3-BrPA primarily inhibited GAPDH activity, while shRNA inhibited both activity and expression.
- GAPDH inhibition induced apoptosis in tumor cells.
- A positive correlation was observed between GAPDH upregulation and c-jun expression in human HCC samples.
Conclusions:
- Percutaneous injection of GAPDH antagonists effectively inhibits HCC tumor progression in a preclinical model.
- Targeting GAPDH induces apoptosis, highlighting its therapeutic potential for human HCC.
- The correlation with c-jun suggests a potential molecular mechanism for GAPDH's role in HCC.
