Opposing Roles of the Forkhead Box Factors FoxM1 and FoxA2 in Liver Cancer

Chand, Vaibhav; Pandey, Ankur; Kopanja, Dragana; Guzman, Grace; Raychaudhuri, Pradip

doi:10.1158/1541-7786.mcr-18-0968

Cited by 17 publications

(13 citation statements)

References 33 publications

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“…Not only that, it was also found that FOXM1 contributes to tumor angiogenesis in the study of colorectal and gastric cancer [23, 32]. In previous studies, there was a large amount of evidence that FOXM1 directly or indirectly affects the occurrence and development of HCC, which is in line with our results [27–29, 33–39]. In addition, in an in vivo study of HCC, the growth of tumors in mice with FOXM1 deficiency was completely stagnated, suggesting that FOXM1 has the potential to become an independent biomarker of HCC [31].…”

Section: Discussionsupporting

confidence: 91%

Based on Integrated Bioinformatics Analysis Identification of Biomarkers in Hepatocellular Carcinoma Patients from Different Regions

Teng

Wang

Liu

et al. 2019

BioMed Research International

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Accumulating statistics have shown that liver cancer causes the second highest mortality rate of cancer-related deaths worldwide, of which 80% is hepatocellular carcinoma (HCC). Given the underlying molecular mechanism of HCC pathology is not fully understood yet, identification of reliable predictive biomarkers is more applicable to improve patients' outcomes. The results of principal component analysis (PCA) showed that the grouped data from 1557 samples in Gene Expression Omnibus (GEO) came from different populations, and the mean tumor purity of tumor tissues was 0.765 through the estimate package in R software. After integrating the differentially expressed genes (DEGs), we finally got 266 genes. Then, the protein-protein interaction (PPI) network was established based on these DEGs, which contained 240 nodes and 1747 edges. FOXM1 was the core gene in module 1 and highly associated with FOXM1 transcription factor network pathway, while FTCD was the core gene in module 2 and was enriched in the metabolism of amino acids and derivatives. The expression levels of hub genes were in line with The Cancer Genome Atlas (TCGA) database. Meanwhile, there were certain correlations among the top ten genes in the up- and downregulated DEGs. Finally, Kaplan–Meier curves and receiver operating characteristic (ROC) curves were plotted for the top five genes in PPI. Apart from CDKN3, the others were closely concerned with overall survival. In this study, we detected the potential biomarkers and their involved biological processes, which would provide a new train of thought for clinical diagnosis and treatment.

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Section: Discussionsupporting

confidence: 91%

Based on Integrated Bioinformatics Analysis Identification of Biomarkers in Hepatocellular Carcinoma Patients from Different Regions

Teng

Wang

Liu

et al. 2019

BioMed Research International

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“…Interestingly, SP1 [ 19 ], E2F3 [ 32 ] and YAP1 [ 33 ] previously reported as important regulators/interactors of HELLS and E2F7 as an important mediator of P53 target gene repression [ 34 , 35 ] were not altered at the transcript level under Nutlin-3a treatment. However, as the most strikingly downregulated TF with a link to P53/P21 [ 36 ], and high relevance in liver cancer [ 37 , 38 , 39 , 40 ] we identified FOXM1 ( Figure 5 A and Table S1 ). Consistent with previous findings in HepG2 [ 36 ] we could validate a strong downregulation of FOXM1 protein and mRNA upon Nutlin-3a treatment also in HUH6 and Sk-Hep1 cells ( Figure 5 B–E).…”

Section: Resultsmentioning

confidence: 99%

HELLS Is Negatively Regulated by Wild-Type P53 in Liver Cancer by a Mechanism Involving P21 and FOXM1

Schuller

Sieker

Riemenschneider

et al. 2022

Cancers

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The major tumor suppressor P53 (TP53) acts primarily as a transcription factor by activating or repressing subsets of its numerous target genes, resulting in different cellular outcomes (e.g., cell cycle arrest, apoptosis and senescence). P53-dependent gene regulation is linked to several aspects of chromatin remodeling; however, regulation of chromatin-modifying enzymes by P53 is poorly understood in hepatocarcinogenesis. Herein, we identified Helicase, lymphoid specific (HELLS), a major epigenetic regulator in liver cancer, as a strong and selective P53 repression target within the SNF2-like helicase family. The underlying regulatory mechanism involved P53-dependent induction of P21 (CDKN1A), leading to repression of Forkhead Box Protein M1 (FOXM1) that in turn resulted in downregulation of HELLS expression. Supporting our in vitro data, we found higher expression of HELLS in murine HCCs arising in a Trp53−/− background compared to Trp53+/+ HCCs as well as a strong and highly significant correlation between HELLS and FOXM1 expression in different HCC patient cohorts. Our data suggest that functional or mutational inactivation of P53 substantially contributes to overexpression of HELLS in HCC patients and indicates a previously unstudied aspect of P53′s ability to suppress liver cancer formation.

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“…FOXM1 is a transcription factor that regulates cell proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis, and apoptosis [ 10 , 11 , 20 ]. Indeed, previous studies have reported that the increased expression of FOXM1 affects tumor growth and drug resistance in various solid tumors [ 21 , 22 , 23 , 24 ]. In this study, we clarified that FOXM1 was retained by dispersed chromatin at the M phase, when the bulk of DNA-binding proteins are excluded from condensed chromosomes [ 25 ], as analyzed by super-resolution microscopy image analysis.…”

Section: Discussionmentioning

confidence: 99%

FOXM1 Is a Novel Molecular Target of AFP-Positive Hepatocellular Carcinoma Abrogated by Proteasome Inhibition

Okada

Yamashita

et al. 2022

IJMS

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Alpha-fetoprotein (AFP) is an oncofetal protein that is elevated in a subset of hepatocellular carcinoma (HCC) with poor prognosis, but the molecular target activated in AFP-positive HCC remains elusive. Here, we demonstrated that the transcription factor forkhead box M1 (FOXM1) is upregulated in AFP-positive HCC. We found that FOXM1 expression was highly elevated in approximately 40% of HCC cases, and FOXM1-high HCC was associated with high serum AFP levels, a high frequency of microscopic portal vein invasion, and poor prognosis. A transcriptome and pathway analysis revealed the activation of the mitotic cell cycle and the inactivation of mature hepatocyte metabolism function in FOXM1-high HCC. The knockdown of FOXM1 reduced AFP expression and induced G2/M cell cycle arrest. We further identified that the proteasome inhibitor carfilzomib attenuated FOXM1 protein expression and suppressed cell proliferation in AFP-positive HCC cells. Carfilzomib in combination with vascular endothelial growth factor receptor 2 (VEGFR2) blockade significantly prolonged survival by suppressing AFP-positive HCC growth in a subcutaneous tumor xenotransplantation model. These data indicated that FOXM1 plays a pivotal role in the proliferation of AFP-positive liver cancer cells. Carfilzomib can effectively inhibit FOXM1 expression to inhibit tumor growth and could be a novel therapeutic option in patients with AFP-positive HCC who receive anti-VEGFR2 antibodies.

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Opposing Roles of the Forkhead Box Factors FoxM1 and FoxA2 in Liver Cancer

Cited by 17 publications

References 33 publications

Based on Integrated Bioinformatics Analysis Identification of Biomarkers in Hepatocellular Carcinoma Patients from Different Regions

Based on Integrated Bioinformatics Analysis Identification of Biomarkers in Hepatocellular Carcinoma Patients from Different Regions

HELLS Is Negatively Regulated by Wild-Type P53 in Liver Cancer by a Mechanism Involving P21 and FOXM1

FOXM1 Is a Novel Molecular Target of AFP-Positive Hepatocellular Carcinoma Abrogated by Proteasome Inhibition

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