Progenitor-derived hepatocellular carcinoma model in the rat

Area of Science:

• Hepatocellular Carcinoma (HCC) Pathogenesis
• Cancer Stem Cell Biology
• Molecular Oncology

Background:

• Human hepatocellular carcinoma (HCC) exhibits significant heterogeneity, potentially arising from different cell types like hepatocytes or adult stem/progenitor cells.
• Understanding the cell of origin is crucial for deciphering HCC heterogeneity and developing targeted therapies.
• The resistant hepatocyte (RH) model provides a platform to study the molecular mechanisms of preneoplastic lesion progression.

Purpose of the Study:

• To investigate the molecular mechanisms driving the fate of enzyme-altered preneoplastic lesions in the rat RH model.
• To identify molecular markers associated with different HCC subgroups and their clinical outcomes.
• To evaluate the utility of the RH model for studying stem/progenitor-derived HCC.

Main Methods:

• Microdissection of 60 samples (focal lesions, adenomas, early and advanced HCCs) from the RH model.
• Global gene expression profiling and immunohistochemical evaluation (CK19).
• Unsupervised hierarchical clustering, supervised analysis, gene connectivity tools, and comparative functional genomics.

Main Results:

• Cytokeratin 19 (CK19) expression was detected in approximately 50% of persistent nodules and all HCCs, with 14% of remodeling nodules being CK19(+).
• Gene expression profiling clustered samples based on CK19 expression, identifying a predominance of the AP-1/JUN network in CK19(+) lesions.
• CK19(+) early lesions and advanced HCCs clustered with human HCCs of poor prognosis; CK19-associated gene signatures predicted patient survival and recurrence.

Conclusions:

• CK19 serves as a prognostic marker for early neoplastic lesions, suggesting progenitor derivation of HCC in the rat RH model.
• CK19-associated gene signatures can stratify HCC patients by clinical prognosis.
• The RH model is valuable for investigating stem/progenitor-derived HCC.