Foxm1 Expression in Prostate Epithelial Cells Is Essential for Prostate Carcinogenesis

Cai, Yuqi; Balli, David; Ustiyan, Vladimir; Fulford, Logan; Hiller, A.; Misetic, Vinko; Zhang, Yufang; Paluch, Andrew M.; Waltz, Susan E.; Kasper, Susan; Kalin, Tanya V.

doi:10.1074/jbc.m113.455089

Cited by 54 publications

(62 citation statements)

References 60 publications

(56 reference statements)

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“…Since Foxm1 is up-regulated in mouse and human prostate cancers and is required for prostate carcinogenesis [8], [10], we tested whether SPDEF inhibits Foxm1. In transgenic TRAMP/SPDEF OE mice, overexpression of SPDEF in prostate decreased Foxm1 mRNA and protein (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we established that prostate epithelial-specific expression of Foxm1 is required for prostate carcinogenesis. Deletion of Foxm1 from prostate epithelial cells in PB-Cre/Foxm1 fl/fl /TRAMP mice prevented prostate carcinogenesis but did not change SPDEF levels [10]. Critical role of Foxm1 in proliferation of prostate tumor cells was confirmed in orthotopic model using Foxm1-deficient MycCap prostate adenocarcinoma cells [10].…”

Section: Discussionmentioning

confidence: 97%

“…Deletion of Foxm1 from prostate epithelial cells in PB-Cre/Foxm1 fl/fl /TRAMP mice prevented prostate carcinogenesis but did not change SPDEF levels [10]. Critical role of Foxm1 in proliferation of prostate tumor cells was confirmed in orthotopic model using Foxm1-deficient MycCap prostate adenocarcinoma cells [10]. Therefore, understanding the mechanisms regulating Foxm1 is particularly relevant to the pathogenesis of prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

“…TRAMP-C2R3 (termed as TRAMP C2) prostate adenocarcinoma cells [10] and MycCap cells prostate adenocarcinoma cells [43] were transduced with lentiviruses. After two days, GFP expressing cells were sorted using flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

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SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene

et al. 2014

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SAM-pointed domain-containing ETS transcription factor (SPDEF) is expressed in normal prostate epithelium. While its expression changes during prostate carcinogenesis (PCa), the role of SPDEF in prostate cancer remains controversial due to the lack of genetic mouse models. In present study, we generated transgenic mice with the loss- or gain-of-function of SPDEF in prostate epithelium to demonstrate that SPDEF functions as tumor suppressor in prostate cancer. Loss of SPDEF increased cancer progression and tumor cell proliferation, whereas over-expression of SPDEF in prostate epithelium inhibited carcinogenesis and reduced tumor cell proliferation in vivo and in vitro. Transgenic over-expression of SPDEF inhibited mRNA and protein levels of Foxm1, a transcription factor critical for tumor cell proliferation, and reduced expression of Foxm1 target genes, including Cdc25b, Cyclin B1, Cyclin A2, Plk-1, AuroraB, CKS1 and Topo2alpha. Deletion of SPDEF in transgenic mice and cultures prostate tumor cells increased expression of Foxm1 and its target genes. Furthermore, an inverse correlation between SPDEF and Foxm1 levels was found in human prostate cancers. The two-gene signature of low SPDEF and high FoxM1 predicted poor survival in prostate cancer patients. Mechanistically, SPDEF bound to, and inhibited transcriptional activity of Foxm1 promoter by interfering with the ability of Foxm1 to activate its own promoter through auto-regulatory site located in the −745/−660 bp Foxm1 promoter region. Re-expression of Foxm1 restored cellular proliferation in the SPDEF-positive cancer cells and rescued progression of SPDEF-positive tumors in mouse prostates. Altogether, SPDEF inhibits prostate carcinogenesis by preventing Foxm1-regulated proliferation of prostate tumor cells. The present study identified novel crosstalk between SPDEF tumor suppressor and Foxm1 oncogene and demonstrated that this crosstalk is required for tumor cell proliferation during progression of prostate cancer in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene

et al. 2014

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“…erase reporter (Ϫ5.3 kb Foxf1 ϩ 3Ј response element) and Foxf2 luciferase reporter (six repeats of Foxf2-binding sequence) genes were transfected into U2OS cells, and luciferase assays were performed as described previously (46,49). Mammalian two-hybrid assays utilizing SRF fused to the GAL4 DNA binding domain and myocardin fused to the GAL4 activation domain were performed as described previously (50).…”

Section: Gene (Promoter Region) Forward Primer (5 To 3) Reverse Primementioning

confidence: 99%

Forkhead Box F2 Regulation of Platelet-derived Growth Factor and Myocardin/Serum Response Factor Signaling Is Essential for Intestinal Development

Bolte

Ren

Tomley

et al. 2015

Journal of Biological Chemistry

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Background: Transcriptional regulation of smooth muscle cells is an understudied component of intestinal development and physiology. Results: Foxf2 deletion from smooth muscle causes intestinal malformations and colon remodeling. Conclusion: Foxf2 regulation of PDGF and myocardin/SRF signaling is essential for intestinal development and homeostasis. Significance: Better understanding of transcriptional mechanisms regulating postnatal intestine development and homeostasis may provide therapeutic approaches for congenital and acquired gastrointestinal diseases.

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Identification of core genes and outcomes in hepatocellular carcinoma by bioinformatics analysis

Shen

Kong

Qiu

et al. 2018

J of Cellular Biochemistry

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Hepatocellular carcinoma (HCC) is the most common malignant liver disease in the world. However, the mechanistic relationships among various genes and signaling pathways are still largely unclear. In this study, we aimed to elucidate potential core candidate genes and pathways in HCC. The expression profiles GSE14520, GSE25097, GSE29721, and GSE62232, which cover 606 tumor and 550 nontumour samples, were downloaded from the Gene Expression Omnibus (GEO) database. Furthermore, HCC RNA-seq datasets were also downloaded from the Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were filtered using R software, and we performed gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis using the online databases DAVID 6.8 and KOBAS 3.0. Furthermore, the protein-protein interaction (PPI) network complex of these DEGs was constructed by Cytoscape software, the molecular complex detection (MCODE) plug-in and the online database STRING. First, a total of 173 DEGs (41 upregulated and 132 downregulated) were identified that were aberrantly expressed in both the GEO and TCGA datasets. Second, GO analysis revealed that most of the DEGs were significantly enriched in extracellular exosomes, cytosol, extracellular region, and extracellular space. Signaling pathway analysis indicated that the DEGs had common pathways in metabolism-related pathways, cell cycle, and biological oxidations. Third, 146 nodes were identified from the DEG PPI network complex, and two important modules with a high degree were detected using the MCODE plug-in. In addition, 10 core genes were identified, TOP2A, NDC80, FOXM1, HMMR, KNTC1, PTTG1, FEN1, RFC4, SMC4, and PRC1. Finally, Kaplan-Meier analysis of overall survival and correlation analysis were applied to these genes. The abovementioned findings indicate that the identified core genes and pathways in this bioinformatics analysis could significantly enrich our understanding of the development and recurrence of HCC; furthermore, these candidate genes and pathways could be therapeutic targets for HCC treatment. K E Y W O R D S bioinformatical analysis, differentially expressed genes (DEGs), hepatocellular carcinoma (HCC), pathways J Cell Biochem. 2019;120:10069-10081.wileyonlinelibrary.com/journal/jcb

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Foxm1 Expression in Prostate Epithelial Cells Is Essential for Prostate Carcinogenesis

Cited by 54 publications

References 60 publications

SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene

SPDEF Inhibits Prostate Carcinogenesis by Disrupting a Positive Feedback Loop in Regulation of the Foxm1 Oncogene

Forkhead Box F2 Regulation of Platelet-derived Growth Factor and Myocardin/Serum Response Factor Signaling Is Essential for Intestinal Development

Identification of core genes and outcomes in hepatocellular carcinoma by bioinformatics analysis

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