Abstract

Background: Previous studies indicate unrestrained cell cycle progression in liver lesions from susceptible F344 rats and block of G1-S transition in corresponding lesions from BN resistant rats.

Aim: Here, we assessed the role of the Forkhead box M1B (FOXM1) gene during hepatocarcinogenesis in both rat models and human HCC (HCC).

Methods and results: FOXM1 and its targets levels were determined by immunoprecipitation and real-time PCR analyses in rat and human samples. FOXM1 function was investigated by either FOXM1 silencing or overexpression in human HCC cell lines. Activation of FOXM1 and its targets (Aurora A, Cdc2, Cyclin B1, Nek2) occurred earlier and was most pronounced in liver lesions from F344 than BN rats, leading to highest Cdc2-Cyclin B1 complexes (implying highest G2-M transition) in F344 rats. In human HCC, FOXM1 progressively increased from surrounding non-tumorous livers to HCC, reaching the highest levels in tumors with poorer prognosis (as defined by patients’ survival length). Furthermore, expression levels of FOXM1 directly correlated with proliferation index, genomic instability rate, and microvessel density, and inversely with apoptosis. FOXM1 upregulation was due to ERK and GLI1 combined activity and its overexpression resulted in increased proliferation and angiogenesis and reduced apoptosis in human HCC cell lines. Conversely, FOXM1 suppression led to decreased ERK activity, reduced proliferation and angiogenesis and massive apoptosis of human HCC cell lines.

Conclusions: FOXM1 upregulation is associated with the acquisition of a susceptible phenotype in rats and influences human HCC development and prognosis.