Forkhead box M1B is a determinant of rat susceptibility to hepatocarcinogenesis and sustains ERK activity in human HCC

Abstract

Forkhead box M1B is a determinant of rat susceptibility to hepatocarcinogenesis and sustains ERK activity in human HCC ABSTRACT Background and aim: Previous studies indicate unrestrained cell cycle progression in liver lesions from hepatocarcinogenesis-susceptible Fisher 344 (F344) rats and a block of G 1 -S transition in corresponding lesions from resistant Brown Norway (BN) rats. Here, the role of the Forkhead box M1B (FOXM1) gene during hepatocarcinogenesis in both rat models and human hepatocellular carcinoma (HCC) was assessed. Methods and results: Levels of FOXM1 and its targets 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 Kinose A, Cdc2, cyclin B1, Nek2) occurred earlier and was most pronounced in liver lesions from F344 than BN rats, leading to the highest number of Cdc2-cyclin B1 complexes (implying the highest G 2 -M transition) in F344 rats. In human HCC, the level of FOXM1 progressively increased from surrounding nontumorous livers to HCC, reaching the highest levels in tumours with poorer prognosis (as defined by patients' length of survival). Furthermore, expression levels of FOXM1 directly correlated with the proliferation index, genomic instability rate and microvessel density, and inversely with apoptosis. FOXM1 upregulation was due to extracellular signal-regulated kinase (ERK) and glioblastoma-associated oncogene 1 (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.

Overexpression of Forkhead box M1 protein associates with aggressive tumor features and poor prognosis of hepatocellular carcinoma

“…therefore, validity of the prognostic value of FoXM1 expression could be at least helpful to identify those patients who would benefit from closer monitoring and from improved treatment strategies. previous studies demonstrated that FoXM1 expression was inversely associated with survival of Hcc patients (18). In line with the current data, we found that expression of FoXM1 was a strong independent predictor of os for Hcc patients.…”

“…this association strongly suggests that FoXM1 could be further evaluated as a biomarker to identify subsets of Hcc tumors with aggressive phenotype. nevertheless, a recent study has documented discrepant data that no significant correlation was observed between FoXM1 expression and clinicopathological parameters in 58 western Hcc patients (18). possible explanations for this discrepancy include differences in detection method for FoXM1 protein, cohort size and patient population between that and our studies.…”

“…of the Fox members, Forkhead box M1 (FoXM1) protein shows some uniqueness, being abundantly expressed in the transformed cells and a variety of human cancers but undetectable in various differentiated cells and quiescent adult tissues (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). It has recently been shown that conditional deletion of FoXM1 expression in mouse hepatocytes resulted in failure in cell proliferation and resistance to liver tumor induction by diethylnitrosamine (Den)/phenobarbital (PB) (6).…”

Targeting FoxM1 transcription factor in T-cell acute lymphoblastic leukemia cell line

“…FoxM1 has been shown to activate the oncogenic pathways that are important in carcinogenesis such as mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), phosphatdyl inositol 3-kinase (PI3k)/Akt), nuclear factor kappa-B and sonic hedgehog (SHH) [33][34][35][36][37]. Moreover, FoxM1 has been shown to decrease the gene expression levels of the tumor suppressor genes and also the genes involved in cellular senescence like p53 and p21 cip1 [20,38].…”

Knockdown of FoxM1 by siRNA interference decreases cell proliferation, induces cell cycle arrest and inhibits cell invasion in MHCC-97H cells in vitro

“…The data above indicate that FoxM1 is a potential specific target for HCC therapy. Interestingly, a recent study showed that lower expression of FoxM1 in HCC was associated with prolonged disease-free survival after curative liver resection and validated FoxM1 as a prognostic marker for HCC [15] .…”