Abstract
BackgroundForkhead box M1 (FOXM1) is a proliferation-associated transcription factor of the forkhead box proteins superfamily, which includes four isoforms FOXM1a, b, c, and d. FOXM1 has been implicated in hepatocellular carcinoma (HCC) progression, but the underlying molecular mechanism remains elusive. In this study, we aim to clarify the molecular basis for FOXM1-mediated HCC progression.MethodsBioinformatic analysis was used to explore the differentially expressed genes predicting HCC proliferation. The expression of FOXM1 and kinesin family member (KIF)4A was confirmed by western blotting and immunohistochemistry in HCC tissues. Kaplan-Meier survival analysis was conducted to analyze the clinical impact of FOXM1 and KIF4A on HCC. The effect of FOXM1 on the regulation of KIF4A expression was studied in cell biology experiments. The interaction between KIF4A and FOXM1 was analyzed by chromatin immunoprecipitation and luciferase experiments. A series of experiments was performed to explore the functions of FOXM1/KIF4A in HCC progression, such as cell proliferation, cell growth, cell viability, and cell cycle. A xenograft mouse model was used to explore the regulatory effect of FOXM1-KIF4A axis on HCC tumor growth.ResultsFOXM1 and KIF4A were overexpressed in human primary HCC tissues compared to that in matched adjacent normal liver tissue and are significant risk factors for HCC recurrence and shorter survival. We found that KIF4A was dominantly regulated by FOXM1c among the four isoforms, and further identified KIF4A as a direct downstream target of FOXM1c. Inhibiting FOXM1 decreased KIF4A expression in HCC cells, whereas its overexpression had the opposite effect. FOXM1-induced HCC cell proliferation was dependent on elevated KIF4A expression as KIF4A knockdown abolished FOXM1-induced proliferation of HCC cells both in vitro and in vivo.ConclusionThe FOXM1–KIF4A axis mediates human HCC progression and is a potential therapeutic target for HCC treatment.
Highlights
Forkhead box M1 (FOXM1) is a proliferation-associated transcription factor of the forkhead box proteins superfamily, which includes four isoforms FOXM1a, b, c, and d
Cluster analysis revealed that 18 of the upregulated genes including KIF4A, FOXM1, KIF20A, and Centromere protein F (CENPF) are linked to hepatocellular carcinoma (HCC) cell proliferation (Fig. 1b, c)
A bioinformatics analysis of The Cancer Genome Atlas (TCGA) data confirmed the upregulation of FOXM1 and KIF4A (Additional file 2: Figure S1a, b) and the two FOXM1 target genes CENPF and KIF20A (Additional file 2: Figure S1c), and a correlation analysis of cBioPortal for Cancer Genomics data showed a positive correlation between FOXM1 and KIF4A expression levels (Additional file 2: Figure S1d)
Summary
Forkhead box M1 (FOXM1) is a proliferation-associated transcription factor of the forkhead box proteins superfamily, which includes four isoforms FOXM1a, b, c, and d. FOXM1 is regulated by the Hedgehog [5], p53 [6], Ras [7], and FoxO3 [8] signaling pathways and activates downstream targets including those that regulate the cell cycle and proliferation such as centromere protein (CENP) F, cyclin B1 (CCNB1), and kinesin family member (KIF)20A, among others [9]. FOXM1 has been identified in humans as a proto-oncogene [3, 10] whose overexpression is associated with the development of basal cell carcinoma under Hedgehog signaling [11]. Various proteasome inhibitors (e.g., siomycin A and thiostrepton) targeting FOXM1 are used in cancer chemotherapy; they are associated with severe side effects [15]
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