Genetic Predisposition to Hepatocellular Carcinoma.

Area of Science:

• Hepatology
• Molecular Biology
• Cancer Research

Background:

• Genetically susceptible (F344) and resistant (BN) rats model human hepatocellular carcinoma (HCC) with distinct prognoses (HCCB vs. HCCP).
• Ubiquitin-mediated proteolysis of DUSP1 (dual-specificity phosphatase 1) allows ERK (extracellular signal-regulated kinase) overactivation, a hallmark of HCC progression.
• FOXM1 (Forkhead box M1), CKS1 (CDC28 protein kinase regulatory subunit 1B), and SKP2 (S-phase kinase-associated protein 2) are implicated in HCC pathogenesis.

Purpose of the Study:

• To investigate the molecular alterations underlying genetic predisposition to HCC in rat models.
• To identify molecular markers and therapeutic targets for human HCC based on comparative genomics with rat models.
• To elucidate the role of specific genes and pathways in HCC progression and prognosis.

Main Methods:

• Comparative gene expression analysis of liver preneoplastic and neoplastic lesions in F344 and BN rats against human HCC datasets.
• Hierarchical supervised analysis of 6132 common genes between human and rat liver.
• Investigation of DUSP1, ERK, FOXM1, GNMT (glycine N-methyltransferase), and MYBL2 (MYB proto-oncogene-like 2) expression and function.

Main Results:

• F344 rat lesions cluster with human HCCP, while BN rat lesions cluster with human HCCB, validating the models.
• DUSP1 downregulation and ERK1/2 overexpression in F344 lesions and human HCCP sustain SKP2-CKS1 activity via FOXM1.
• MYBL2 upregulation correlates with proliferation and angiogenesis while negatively correlating with apoptosis during HCC progression.

Conclusions:

• Rat models accurately reflect human HCC subtypes, offering valuable platforms for HCC research.
• DUSP1 is a prognostic marker, and ERK, CKS1, SKP2, and MYBL2 are potential therapeutic targets for HCC.
• Gene expression patterns differentiate susceptible and resistant phenotypes, providing insights into HCC development.