FOXO1

Gene Summary

Gene:FOXO1; forkhead box O1
Aliases: FKH1, FKHR, FOXO1A
Location:13q14.1
Summary:This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation. Translocation of this gene with PAX3 has been associated with alveolar rhabdomyosarcoma. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:forkhead box protein O1
HPRD
Source:NCBIAccessed: 26 August, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 26 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 26 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
-FOXO1 and Alveolar Rhabdomyosarcoma View Publications102
Urinary System CancersFOXO1 and Urinary System Cancers View Publications47
Breast CancerFOXO1 and Breast Cancer View Publications25
Skin CancerFOXO1 and Skin Cancer View Publications1
Thyroid CancerFOXO1 and Thyroid Cancer View Publications1
Rhabdomyosarcomat(2;13)(q35;q14) in Rhabdomyosarcoma
Alveolar rhabdomyosarcoma, a malignant tumour of skeletal muscle usually found in children and young adults, is characterised by a chromosomal translocation of the PAX3-FKHR genes: t(2;13)(q35;q14).
Rhabdomyosarcomat(1;13)(p36;q14) in Rhabdomyosarcoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FOXO1 (cancer-related)

Leung WK, He M, Chan AW, et al.
Wnt/β-Catenin activates MiR-183/96/182 expression in hepatocellular carcinoma that promotes cell invasion.
Cancer Lett. 2015; 362(1):97-105 [PubMed] Related Publications
Nearly 50% of known miRNAs are found in clusters and transcribed as polycistronic transcripts. In this study, we showed that over-expression of miR-183/96/182 cluster is frequent in hepatocellular carcinoma (HCC), a highly aggressive malignancy that is commonly fatal. In a cohort of HCC patients (n = 81), miR-183/96/182 up-regulation correlated with metastatic features including presence of microvascular invasion, advanced tumor differentiation, and shorter recurrence-free survival. Univariate and multivariate analyses further showed miR-183/96/182 over-expression represented an independent prognostic factor (Relative Risk: 2.0471; P = 0.0289). Functional investigation using siRNA against miR-183/96/182 in two invasive HCC cells indicated significant inhibition on cell migration and invasion without affecting cell viability. Forkhead boxO1 (FOXO1) was further validated as a downstream target of these three miRNAs. In investigating the regulatory mechanism underlining miR-183/96/182 over-expression, a direct interaction of CTNNB1 on the promoter region was confirmed by ChIP-PCR and luciferase reporter validations. Knockdown of CTNNB1 also showed concordant down-regulations of miR-183, -96 and -182, and the re-expression of FOXO1. Our findings demonstrated that over-expression of miR-183/96/182 confers an oncogenic function in HCC cell dissemination, and could serve as an independent prognostic predictor for HCC patients.

Lagutina IV, Valentine V, Picchione F, et al.
Modeling of the human alveolar rhabdomyosarcoma Pax3-Foxo1 chromosome translocation in mouse myoblasts using CRISPR-Cas9 nuclease.
PLoS Genet. 2015; 11(2):e1004951 [PubMed] Free Access to Full Article Related Publications
Many recurrent chromosome translocations in cancer result in the generation of fusion genes that are directly implicated in the tumorigenic process. Precise modeling of the effects of cancer fusion genes in mice has been inaccurate, as constructs of fusion genes often completely or partially lack the correct regulatory sequences. The reciprocal t(2;13)(q36.1;q14.1) in human alveolar rhabdomyosarcoma (A-RMS) creates a pathognomonic PAX3-FOXO1 fusion gene. In vivo mimicking of this translocation in mice is complicated by the fact that Pax3 and Foxo1 are in opposite orientation on their respective chromosomes, precluding formation of a functional Pax3-Foxo1 fusion via a simple translocation. To circumvent this problem, we irreversibly inverted the orientation of a 4.9 Mb syntenic fragment on chromosome 3, encompassing Foxo1, by using Cre-mediated recombination of two pairs of unrelated oppositely oriented LoxP sites situated at the borders of the syntenic region. We tested if spatial proximity of the Pax3 and Foxo1 loci in myoblasts of mice homozygous for the inversion facilitated Pax3-Foxo1 fusion gene formation upon induction of targeted CRISPR-Cas9 nuclease-induced DNA double strand breaks in Pax3 and Foxo1. Fluorescent in situ hybridization indicated that fore limb myoblasts show a higher frequency of Pax3/Foxo1 co-localization than hind limb myoblasts. Indeed, more fusion genes were generated in fore limb myoblasts via a reciprocal t(1;3), which expressed correctly spliced Pax3-Foxo1 mRNA encoding Pax3-Foxo1 fusion protein. We conclude that locus proximity facilitates chromosome translocation upon induction of DNA double strand breaks. Given that the Pax3-Foxo1 fusion gene will contain all the regulatory sequences necessary for precise regulation of its expression, we propose that CRISPR-Cas9 provides a novel means to faithfully model human diseases caused by chromosome translocation in mice.

De Rosa MC, Caputo M, Zirpoli H, et al.
Identification of Genes Selectively Regulated in Human Hepatoma Cells by Treatment With Dyslipidemic Sera and PUFAs.
J Cell Physiol. 2015; 230(9):2059-66 [PubMed] Related Publications
Serum composition is linked to metabolic diseases not only to understand their pathogenesis but also for diagnostic purposes. Quality and quantity of nutritional intake can affect disease risk and serum composition. It is then possible that diet derived serum components directly affect pathogenetic mechanisms. To identify involved factors, we evaluated the effect on gene expression of direct addition of dyslipidemic human serum samples to cultured human hepatoma cells (HepG2). Sera were selected on the basis of cholesterol level, considering this parameter as mostly linked to dietary intake. Cells were treated with 32 sera from hypercholesterolemic and normocholesterolemic subjects to identify differentially regulated mRNAs using DNA microarray analysis. We identified several mRNAs with the highest modulations in cells treated with dyslipidemic sera versus cells treated with normal sera. Since the two serum groups had variable polyunsaturated fatty acids (PUFAs) contents, selected mRNAs were further assessed for their regulation by docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AA). Four genes resulted both affected by serum composition and PUFAs: 3-hydroxy-3-methylglutaryl-CoenzymeA synthase 2 (HMGCS2), glutathione S-transferase alpha 1 (GSTA1), liver expressed antimicrobial peptide 2 (LEAP2) and apolipoprotein M (ApoM). HMGCS2 expression appears the most relevant and was also found modulated via transcription factors peroxysome proliferator activated receptor α (PPARα) and forkhead box O1 (FoxO1). Our data indicate that expression levels of the selected mRNAs, primarily of HMGCS2, could represent a reference of nutritional intake, PUFAs effects and dyslipidemic diseases pathogenesis.

Han DF, Zhang JX, Wei WJ, et al.
Fenofibrate induces G0/G1 phase arrest by modulating the PPARα/FoxO1/p27 kip pathway in human glioblastoma cells.
Tumour Biol. 2015; 36(5):3823-9 [PubMed] Related Publications
Fenofibrate, a fibric acid derivative, is known to possess lipid-lowering effects. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcriptional activity has been reported to exhibit anticancer effects, the underlying mechanisms are poorly understood. In this study, we investigated the mechanisms behind the antiproliferative effects of fenofibrate in U87MG cells (human glioma cell line) using the WST-8 Cell Proliferation Assay Kit. Furthermore, we examined genome-wide gene expression profiles and molecular networks using the DAVID online software. Fenofibrate reduced the expression of 405 genes and increased the expression of 2280 genes. DAVID analysis suggested that fenofibrate significantly affected cell cycle progression and pathways involved in cancer, including the mTOR signaling pathway and insulin signaling pathway. Results of flow cytometry analysis indicated that fenofibrate induced cell cycle G0/G1 arrest in U87MG cells. Furthermore, we identified the FoxO1-p27(kip) signaling axis to be involved in fenofibrate-induced cell cycle arrest. Our findings suggest that in addition to its known lipid-lowering effects, fenofibrate may be used as an antitumor agent in glioma therapy.

Judge SM, Wu CL, Beharry AW, et al.
Genome-wide identification of FoxO-dependent gene networks in skeletal muscle during C26 cancer cachexia.
BMC Cancer. 2014; 14:997 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Evidence from cachectic cancer patients and animal models of cancer cachexia supports the involvement of Forkhead box O (FoxO) transcription factors in driving cancer-induced skeletal muscle wasting. However, the genome-wide gene networks and associated biological processes regulated by FoxO during cancer cachexia are unknown. We hypothesize that FoxO is a central upstream regulator of diverse gene networks in skeletal muscle during cancer that may act coordinately to promote the wasting phenotype.
METHODS: To inhibit endogenous FoxO DNA-binding, we transduced limb and diaphragm muscles of mice with AAV9 containing the cDNA for a dominant negative (d.n.) FoxO protein (or GFP control). The d.n.FoxO construct consists of only the FoxO3a DNA-binding domain that is highly homologous to that of FoxO1 and FoxO4, and which outcompetes and blocks endogenous FoxO DNA binding. Mice were subsequently inoculated with Colon-26 (C26) cells and muscles harvested 26 days later.
RESULTS: Blocking FoxO prevented C26-induced muscle fiber atrophy of both locomotor muscles and the diaphragm and significantly spared force deficits. This sparing of muscle size and function was associated with the differential regulation of 543 transcripts (out of 2,093) which changed in response to C26. Bioinformatics analysis of upregulated gene transcripts that required FoxO revealed enrichment of the proteasome, AP-1 and IL-6 pathways, and included several atrophy-related transcription factors, including Stat3, Fos, and Cebpb. FoxO was also necessary for the cancer-induced downregulation of several gene transcripts that were enriched for extracellular matrix and sarcomere protein-encoding genes. We validated these findings in limb muscles and the diaphragm through qRT-PCR, and further demonstrate that FoxO1 and/or FoxO3a are sufficient to increase Stat3, Fos, Cebpb, and the C/EBPβ target gene, Ubr2. Analysis of the Cebpb proximal promoter revealed two bona fide FoxO binding elements, which we further establish are necessary for Cebpb promoter activation in response to IL-6, a predominant cytokine in the C26 cancer model.
CONCLUSIONS: These findings provide new evidence that FoxO-dependent transcription is a central node controlling diverse gene networks in skeletal muscle during cancer cachexia, and identifies novel candidate genes and networks for further investigation as causative factors in cancer-induced wasting.

Wang LS, Li L, Li L, et al.
MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors.
Blood. 2015; 125(8):1302-13 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) are key regulators of hematopoietic cell differentiation and may contribute to altered growth of leukemic stem cells. Using microarray-based miRNA profiling, we found that miRNA 486 (miR-486) is significantly upregulated in chronic myeloid leukemia (CML) compared with normal CD34(+) cells, particularly in the megakaryocyte-erythroid progenitor population. miR-486-5p expression increased during erythroid differentiation of both CML and normal CD34(+) cells. Ectopic miR-486-5p expression enhanced in vitro erythroid differentiation of normal CD34(+) cells, whereas miR-486-5p inhibition suppressed normal CD34(+) cell growth in vitro and in vivo and inhibited erythroid differentiation and erythroid cell survival. The effects of miR-486-5p on hematopoietic cell growth and survival are mediated at least in part via regulation of AKT signaling and FOXO1 expression. Using gene expression and bioinformatics analysis, together with functional screening, we identified several novel miR-486-5p target genes that may modulate erythroid differentiation. We further show that increased miR-486-5p expression in CML progenitors is related to both kinase-dependent and kinase-independent mechanisms. Inhibition of miR-486-5p reduced CML progenitor growth and enhanced apoptosis following imatinib treatment. In conclusion, our studies reveal a novel role for miR-486-5p in regulating normal hematopoiesis and of BCR-ABL-induced miR-486-5p overexpression in modulating CML progenitor growth, survival, and drug sensitivity.

Becerikli M, Wieczorek S, Stricker I, et al.
Numerical and structural chromosomal anomalies in undifferentiated pleomorphic sarcoma.
Anticancer Res. 2014; 34(12):7119-27 [PubMed] Related Publications
BACKGROUND: Malignant fibrous histiocytoma (MFH) or undifferentiated pleomorphic sarcoma (UPS) is the most common soft-tissue sarcoma of late adult life. Further advances in genetic characterization are warranted. The aim of this study was to search for numerical and structural chromosomal anomalies in UPS.
MATERIALS AND METHODS: We investigated five sarcoma-specific chromosomal translocations, five oncogene amplifications as well as the numerical karyotype of 19 UPS samples and one UPS/MFH cell line (U2197) using FISH probes on interphase nuclei.
RESULTS: Our results demonstrate that chromosomal translocations involving CHOP, SYT, EWS, FUS and FKHR genes are absent. Furthermore, amplification of ERBB2 (10.5%) and MDM2 (10.5%) was observed whereas the EGFR, C-MYC and N-MYC genes were not amplified. Interestingly, predominant aneuploidies were found in eight chromosomes.
CONCLUSION: The data demonstrate rarity of sarcoma-specific chromosomal breaks and oncogene amplifications in UPS, yet polysomic chromosomes appear more characteristically in this condition.

Lim S, Yoo BK, Kim HS, et al.
Amyloid-β precursor protein promotes cell proliferation and motility of advanced breast cancer.
BMC Cancer. 2014; 14:928 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Amyloid-β precursor protein (APP) is a highly conserved single transmembrane protein that has been linked to Alzheimer disease. Recently, the increased expression of APP in multiple types of cancers has been reported where it has significant correlation with the cancer cell proliferation. However, the function of APP in the pathogenesis of breast cancer has not previously been determined. In this study, we studied the pathological role of APP in breast cancer and revealed its potential mechanism.
METHODS: The expression level of APP in multiple breast cancer cell lines was measured by Western blot analysis and the breast cancer tissue microarray was utilized to analyze the expression pattern of APP in human patient specimens. To interrogate the functional role of APP in cell growth and apoptosis, the effect of APP knockdown in MDA-MB-231 cells were analyzed. Specifically, multiple signal transduction pathways and functional alterations linked to cell survival and motility were examined in in vivo animal model as well as in vitro cell culture with the manipulation of APP expression.
RESULTS: We found that the expression of APP is increased in mouse and human breast cancer cell lines, especially in the cell line possessing higher metastatic potential. Moreover, the analysis of human breast cancer tissues revealed a significant correlation between the level of APP and tumor development. Knockdown of APP (APP-kd) in breast cancer cells caused the retardation of cell growth in vitro and in vivo, with both the induction of p27(kip1) and caspase-3-mediated apoptosis. APP-kd cells also had higher sensitivity to treatment of chemotherapeutic agents, TRAIL and 5-FU. Such anti-tumorigenic effects shown in the APP-kd cells partially came from reduced pro-survival AKT activation in response to IGF-1, leading to activation of key signaling regulators for cell growth, survival, and pro-apoptotic events such as GSK3-β and FOXO1. Notably, knock-down of APP in metastatic breast cancer cells limited cell migration and invasion ability upon stimulation of IGF-1.
CONCLUSION: The present data strongly suggest that the increase of APP expression is causally linked to tumorigenicity as well as invasion of aggressive breast cancer and, therefore, the targeting of APP may be an effective therapy for breast cancer.

Yang XW, Shen GZ, Cao LQ, et al.
MicroRNA-1269 promotes proliferation in human hepatocellular carcinoma via downregulation of FOXO1.
BMC Cancer. 2014; 14:909 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies and a major cause of cancer-related mortality in the world. MicroRNAs (miRNAs) are small, noncoding RNAs that play essential roles in various stages during cancer progression. The aim of the current study was to elucidate the role of miR-1269 in the pathogenesis of HCC.
METHODS: The expression of miR-1269 in HCC cells and tissues were determined by Real-time PCR analysis. Cell viability, colony formation and anchorage-independent growth ability assays were performed to examine cell proliferative capacity and tumorigenicity. Flow cytometry analysis was conducted to determine cell cycle progression. The expression of p21, CyclinD1, phosphorylated Rb, Rb and FOXO1 were examined by Western blotting analysis. Luciferase assay was used to determine whether FOXO1 is the direct target of miR-1269.
RESULTS: miR-1269 was upregulated in HCC cells and tissues. Ectopic miR-1269 expression promoted, but inhibition of miR-1269 reduced, proliferation, tumorigenicity and cell cycle progression of HCC cells. Furthermore, we demonstrated that FOXO1 was a direct target of miR-1269. Suppression of FOXO1 by miR-1269 was associated with dysregulation of p21, cyclin D1, phosphorylated Rb and Ki67 expression, thereby playing an essential role in the growth of HCC cells.
CONCLUSIONS: Our study indicated that overexpression of miR-1269 promotes cell proliferation in HCC through directly suppressing FOXO1, and functions as an oncomiR in HCC.

Horn H, Allmanritter J, Doglioni C, et al.
Fluorescence in situ analysis of soft tissue tumor associated genetic alterations in formalin-fixed paraffin-embedded tissue.
Pathol Res Pract. 2014; 210(12):804-11 [PubMed] Related Publications
No prospective studies are available to date evaluating the combined analysis of chromosomal alterations via interphase FISH in different soft tissue sarcoma (STS) subtypes. We tested 64 consecutive sarcoma specimens with FISH probes to detect aberrations specific for a given STS subtype. We first determined the translocation frequency in the specific STS subtypes in 48 tumors, with the primary pathological diagnosis as the gold standard. Subsequently, to evaluate sensitivity and specificity, all FISH probes were hybridized to 16 STS of hitherto unknown diagnosis. DDIT3 translocations occurred in 8/10 (80%) of myxoid liposarcomas. FOXO1 translocations were noted in 4/4 (100%) of alveolar but in none of 7 embryonal rhabdomyosarcomas. All 15 (100%) Ewing sarcomas/PNET and 4 clear cell sarcomas (4/4) harbored EWSR1 translocations. SS18 rearrangements were demonstrated in 8/9 (89%) synovial sarcomas. MDM2 amplification was noted in 7/8 (88%) atypical lipomatous tumors/well-differentiated and 3/3 (100%) dedifferentiated liposarcomas, respectively, but not in four pleomorphic liposarcomas. Sensitivities and specificities ranged from 80% to 100% and from 93% to 100%, respectively, with the highest values observed for FOXO1 (100% each). We conclude, therefore, that is possible to accurately predict the STS subtype using a panel of different subtype-specific FISH probes, thereby greatly facilitating the differential diagnosis of these tumors.

Norton L, Chen X, Fourcaudot M, et al.
The mechanisms of genome-wide target gene regulation by TCF7L2 in liver cells.
Nucleic Acids Res. 2014; 42(22):13646-61 [PubMed] Free Access to Full Article Related Publications
In the liver Wnt-signaling contributes to the metabolic fate of hepatocytes, but the precise role of the TCF7L2 in this process is unknown. We employed a temporal RNA-Seq approach to examine gene expression 3-96 h following Tcf7l2 silencing in rat hepatoma cells, and combined this with ChIP-Seq to investigate mechanisms of target gene regulation by TCF7L2. Silencing Tcf7l2 led to a time-dependent appearance of 406 differentially expressed genes (DEGs), including key regulators of cellular growth and differentiation, and amino acid, lipid and glucose metabolism. Direct regulation of 149 DEGs was suggested by strong proximal TCF7L2 binding (peak proximity score > 10) and early mRNA expression changes (≤ 18 h). Indirect gene regulation by TCF7L2 likely occurred via alternate transcription factors, including Hnf4a, Foxo1, Cited2, Myc and Lef1, which were differentially expressed following Tcf7l2 knock-down. Tcf7l2-silencing enhanced the expression and chromatin occupancy of HNF4α, and co-siRNA experiments revealed that HNF4α was required for the regulation of a subset of metabolic genes by TCF7L2, particularly those involved in lipid and amino-acid metabolism. Our findings suggest TCF7L2 is an important regulator of the hepatic phenotype, and highlight novel mechanisms of gene regulation by TCF7L2 that involve interplay between multiple hepatic transcriptional pathways.

Thalhammer V, Lopez-Garcia LA, Herrero-Martin D, et al.
PLK1 phosphorylates PAX3-FOXO1, the inhibition of which triggers regression of alveolar Rhabdomyosarcoma.
Cancer Res. 2015; 75(1):98-110 [PubMed] Related Publications
Pediatric tumors harbor very low numbers of somatic mutations and therefore offer few targets to improve therapeutic management with targeted drugs. In particular, outcomes remain dismal for patients with metastatic alveolar rhabdomyosarcoma (aRMS), where the chimeric transcription factor PAX3/7-FOXO1 has been implicated but problematic to target. In this report, we addressed this challenge by developing a two-armed screen for druggable upstream regulatory kinases in the PAX3/7-FOXO1 pathway. Screening libraries of kinome siRNA and small molecules, we defined PLK1 as an upstream-acting regulator. Mechanistically, PLK1 interacted with and phosphorylated PAX3-FOXO1 at the novel site S503, leading to protein stabilization. Notably, PLK1 inhibition led to elevated ubiquitination and rapid proteasomal degradation of the PAX3-FOXO1 chimeric oncoprotein. On this basis, we embarked on a preclinical validation of PLK1 as a target in a xenograft mouse model of aRMS, where the PLK1 inhibitor BI 2536 reduced PAX3-FOXO1-mediated gene expression and elicited tumor regression. Clinically, analysis of human aRMS tumor biopsies documented high PLK1 expression to offer prognostic significance for both event-free survival and overall survival. Taken together, these preclinical studies validate the PLK1-PAX3-FOXO1 axis as a rational target to treat aRMS.

Gao F, Wang W
MicroRNA-96 promotes the proliferation of colorectal cancer cells and targets tumor protein p53 inducible nuclear protein 1, forkhead box protein O1 (FOXO1) and FOXO3a.
Mol Med Rep. 2015; 11(2):1200-6 [PubMed] Related Publications
MicroRNAs (miRNAs) are a conserved class of small, endogenous, non protein-coding RNA molecules that are capable of regulating gene expression at post-transcriptional levels and are involved in diverse cellular processes, including cancer pathogenesis. It has previously been reported that miRNA-96 (miR-96) is overexpressed in human colorectal cancer (CRC). However, the underlying mechanism of miR-96 regulation in CRC remains to be elucidated. In the present study, miR-96 was confirmed to be upregulated in CRC tissues by reverse transcription quantitative polymerase chain reaction. MTT assay, colony formation assay and cell cycle analysis revealed that miR-96 overexpression led to increased tumor cell viability, colony formation ability and cell cycle progression. By contrast, inhibition of miR-96 resulted in the suppression of cell proliferation. It was also demonstrated that miR-96 reduced the messenger RNA and protein expression levels of tumor protein p53 inducible nuclear protein 1 (TP53INP1), forkhead box protein O1 (FOXO1) and FOXO3a, which are closely associated with cell proliferation. A luciferase reporter assay indicated that miR-96 inhibited luciferase intensity controlled by the 3'UTRs of TP53INP1, FOXO1 and FOXO3a. In conclusion, the results of the present study demonstrated that miR-96 contributed to CRC cell growth and that TP53INP1, FOXO1 and FOXO3a were direct targets of miR-96, suggesting that miR-96 may have the potential to be used in the development of miRNA‑based therapies for CRC patients.

Hettmer S, Li Z, Billin AN, et al.
Rhabdomyosarcoma: current challenges and their implications for developing therapies.
Cold Spring Harb Perspect Med. 2014; 4(11):a025650 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called "fusion-positive" tumors) carries exclusive chromosomal translocations that join the DNA-binding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 (previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in <30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusion-positive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate drugs, coalesce advocacy efforts to garner public and industry support, and facilitate collaborative efforts between academia and industry.

Zhao JG, Ren KM, Tang J
Zinc finger protein ZBTB20 promotes cell proliferation in non-small cell lung cancer through repression of FoxO1.
FEBS Lett. 2014; 588(24):4536-42 [PubMed] Related Publications
In the present study, we found that ZBTB20, a member of the POK (POZ and Krüppel) family of transcriptional repressors, was significantly up-regulated in lung cancer tissues, compared with adjacent normal tissues. Our in vitro studies further found that ZBTB20 overexpression promoted, while its inhibition using small interfering RNA suppressed cell proliferation. Consistently, key regulators in cell-cycle progression, such as Cyclin D1, Cyclin E, P21 and P27, were also regulated by ZBTB20. At the molecular level, we further revealed that FoxO1, a tumor suppressor in multiple human cancers, was transcriptionally repressed by ZBTB20. Therefore, our results highlight an important role for ZBTB20 in controlling NSCLC development, which might be helpful to identify potential therapeutic targets for its treatment.

Vogel MJ, Xie L, Guan H, et al.
FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma.
Blood. 2014; 124(20):3118-29 [PubMed] Related Publications
The survival of classical Hodgkin lymphoma (cHL) cells depends on activation of NF-κB, JAK/STAT, and IRF4. Whereas these factors typically induce the master regulator of plasma cell (PC) differentiation PRDM1/BLIMP-1, levels of PRDM1 remain low in cHL. FOXO1, playing a critical role in normal B-cell development, acts as a tumor suppressor in cHL, but has never been associated with induction of PC differentiation. Here we show that FOXO1 directly upregulates the full-length isoform PRDM1α in cHL cell lines. We also observed a positive correlation between FOXO1 and PRDM1 expression levels in primary Hodgkin-Reed-Sternberg cells. Further, we show that PRDM1α acts as a tumor suppressor in cHL at least partially by blocking MYC. Here we provide a link between FOXO1 repression and PRDM1α downregulation in cHL and identify PRDM1α as a tumor suppressor in cHL. The data support a potential role for FOXO transcription factors in normal PC differentiation.

Takayama K, Suzuki T, Fujimura T, et al.
CtBP2 modulates the androgen receptor to promote prostate cancer progression.
Cancer Res. 2014; 74(22):6542-53 [PubMed] Related Publications
The androgen receptor (AR) is the key driver of both early and advanced prostate cancer, making a complete understanding of its regulation important. Here, we report the identification of multiple AR-binding sites in the gene encoding the transcription factor CtBP2 (carboxyl terminal-binding protein), genetic variations of which have been associated with prostate cancer susceptibility. Notably, we found that SNPs in the human CTBP2 gene that were associated with prostate cancer development were correlated with AR-enhancer activity. High CtBP2 expression levels correlated with poor prognosis in patients, whereas CtBP2 silencing reduced tumor growth in a mouse xenograft model of human prostate cancer. Consistent with its function as a transcriptional corepressor, CtBP2 repressed tumor-suppressor genes and AR corepressors in prostate cancer cells, such as NCOR and RIP140, by binding with AR to the promoter enhancers of these genes. Global gene-expression analyses revealed a positive effect on androgen-mediated gene expression, and CtBP2 silencing was found to increase AR interactions with corepressors that limit histone modification. Overall, our results show how CtBP2 contributes to prostate cancer progression by modulating AR and oncogenic signaling.

Zhu H
Targeting forkhead box transcription factors FOXM1 and FOXO in leukemia (Review).
Oncol Rep. 2014; 32(4):1327-34 [PubMed] Related Publications
Deregulation of forkhead box (FOX) proteins has been found in many genetic diseases and malignancies including leukemia. Leukemia is a common neoplastic disease of the blood or bone marrow characterized by the presence of immature leukocytes and is one of the leading causes of death due to cancer. Forkhead transcription factors, FOXM1 and FOXO family members (FOXOs), are important mediators in leukemia development. Aberrant expression of FOXM1 and FOXOs results in leukemogenesis. Usually the expression of FOXM1 is upregulated, whereas the expression of FOXOs is downregulated due to phosphorylation, nuclear exclusion and degradation in leukemia. On the one hand, FOXOs are bona fide tumor suppressors, on the other hand, active FOXOs maintain leukemia stem cells and stimulate drug resistance genes, contributing to leukemogenesis. FOXM1 and FOXOs have been proven to be potential targets for the development of leukemia therapeutics. They are also valuable diagnostic and prognostic markers in leukemia for clinical applications. This review summarizes the present knowledge concerning the molecular mechanisms by which FOXM1 and FOXOs modulate leukemogenesis and leukemia development, the clinical relevance of these FOX proteins in leukemia and related areas that warrant further investigation.

Melis M, Diaz G, Kleiner DE, et al.
Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus-associated hepatocellular carcinoma.
J Transl Med. 2014; 12:230 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The molecular mechanisms whereby hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) remain elusive. We used genomic and molecular techniques to investigate host-virus interactions by studying multiple areas of the same liver from patients with HCC.
METHODS: We compared the gene signature of whole liver tissue (WLT) versus laser capture-microdissected (LCM) hepatocytes along with the intrahepatic expression of HBV. Gene expression profiling was performed on up to 17 WLT specimens obtained at various distances from the tumor center from individual livers of 11 patients with HCC and on selected LCM samples. HBV markers in liver and serum were determined by real-time polymerase chain reaction (PCR) and confocal immunofluorescence.
RESULTS: Analysis of 5 areas of the liver showed a sharp change in gene expression between the immediate perilesional area and tumor periphery that correlated with a significant decrease in the intrahepatic expression of HB surface antigen (HBsAg). The tumor was characterized by a large preponderance of down-regulated genes, mostly involved in the metabolism of lipids and fatty acids, glucose, amino acids and drugs, with down-regulation of pathways involved in the activation of PXR/RXR and PPARα/RXRα nuclear receptors, comprising PGC-1α and FOXO1, two key regulators critically involved not only in the metabolic functions of the liver but also in the life cycle of HBV, acting as essential transcription factors for viral gene expression. These findings were confirmed by gene expression of microdissected hepatocytes. Moreover, LCM of malignant hepatocytes also revealed up-regulation of unique genes associated with cancer and signaling pathways, including two novel HCC-associated cancer testis antigen genes, NUF2 and TTK.
CONCLUSIONS: Integrated gene expression profiling of whole liver tissue with that of microdissected hepatocytes demonstrated that HBV-associated HCC is characterized by a metabolism switch-off and by a significant reduction in HBsAg. LCM proved to be a critical tool to validate gene signatures associated with HCC and to identify genes that may play a role in hepatocarcinogenesis, opening new perspectives for the discovery of novel diagnostic markers and therapeutic targets.

Nagel S, Meyer C, Kaufmann M, et al.
Deregulated FOX genes in Hodgkin lymphoma.
Genes Chromosomes Cancer. 2014; 53(11):917-33 [PubMed] Related Publications
FOX genes encode transcription factors which regulate basic developmental processes during embryogenesis and in the adult. Several FOX genes show deregulated expression in particular malignancies, representing oncogenes or tumor suppressors. Here, we screened six Hodgkin lymphoma (HL) cell lines for FOX gene activity by comparative microarray profiling, revealing overexpression of FOXC1 and FOXD1, and reduced transcription of FOXN3, FOXO1, and FOXP1. In silico expression analyses of these FOX gene candidates in HL patient samples supported the cell line data. Chromosomal analyses demonstrated an amplification of the FOXC1 locus at 6p25 and a gain of the FOXR2 locus at Xp11, indicting genomic aberrations for their upregulation. Comparative expression profiling and ensuing stimulation experiments revealed implementation of the TGFβ- and WNT-signaling pathways in deregulation of FOXD1 and FOXN3. Functional analysis of FOXP1 implicated miR9 and miR34a as upstream regulators and PAX5, TCF3, and RAG2 as downstream targets. A similar exercise for FOXC1 revealed repression of MSX1 and activation of IPO7, both mediating inhibition of the B-cell specific homeobox gene ZHX2. Taken together, our data show that aberrantly expressed FOX genes and their downstream targets are involved in the pathogenesis of HL via deregulation of B-cell differentiation and may represent useful diagnostic markers and/or therapeutic targets.

Abraham J, Nuñez-Álvarez Y, Hettmer S, et al.
Lineage of origin in rhabdomyosarcoma informs pharmacological response.
Genes Dev. 2014; 28(14):1578-91 [PubMed] Free Access to Full Article Related Publications
Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.

Yang J, Li T, Gao C, et al.
FOXO1 3'UTR functions as a ceRNA in repressing the metastases of breast cancer cells via regulating miRNA activity.
FEBS Lett. 2014; 588(17):3218-24 [PubMed] Related Publications
The competitive endogenous RNAs (ceRNAs) are RNA molecules that affect each other's expression through competition for their shared microRNAs (miRNAs). In this study we explored whether FOXO1 3'UTR can function as a ceRNA in repressing epithelial-to-mesenchymal transition (EMT) and metastasis of breast cancer cells via regulating miR-9 activity. We found that miR-9 binds to both the FOXO1- and E-cadherin-3'UTR, indicating that the FOXO1- and E-cadherin-3'UTR can be linked through miR-9. Follow-up analyses showed that there existed a competition of miR-9 between FOXO1 and E-cadherin-3'UTR. Thus FOXO1 3'UTR inhibits the metastases of breast cancer cells via induction of E-cadherin expression. Our results suggest that FOXO1 3'UTR may function as a miRNA-inhibitor in modulating metastasis of breast cancer cells.

Chen D, Goswami CP, Burnett RM, et al.
Cancer affects microRNA expression, release, and function in cardiac and skeletal muscle.
Cancer Res. 2014; 74(16):4270-81 [PubMed] Free Access to Full Article Related Publications
Circulating microRNAs (miRNA) are emerging as important biomarkers of various diseases, including cancer. Intriguingly, circulating levels of several miRNAs are lower in patients with cancer compared with healthy individuals. In this study, we tested the hypothesis that a circulating miRNA might serve as a surrogate of the effects of cancer on miRNA expression or release in distant organs. Here we report that circulating levels of the muscle-enriched miR486 is lower in patients with breast cancer compared with healthy individuals and that this difference is replicated faithfully in MMTV-PyMT and MMTV-Her2 transgenic mouse models of breast cancer. In tumor-bearing mice, levels of miR486 were relatively reduced in muscle, where there was elevated expression of the miR486 target genes PTEN and FOXO1A and dampened signaling through the PI3K/AKT pathway. Skeletal muscle expressed lower levels of the transcription factor MyoD, which controls miR486 expression. Conditioned media (CM) obtained from MMTV-PyMT and MMTV-Her2/Neu tumor cells cultured in vitro were sufficient to elicit reduced levels of miR486 and increased PTEN and FOXO1A expression in C2C12 murine myoblasts. Cytokine analysis implicated tumor necrosis factor α (TNFα) and four additional cytokines as mediators of miR486 expression in CM-treated cells. Because miR486 is a potent modulator of PI3K/AKT signaling and the muscle-enriched transcription factor network in cardiac/skeletal muscle, our findings implicated TNFα-dependent miRNA circuitry in muscle differentiation and survival pathways in cancer.

Xie L, Ritz O, Leithäuser F, et al.
FOXO1 downregulation contributes to the oncogenic program of primary mediastinal B-cell lymphoma.
Oncotarget. 2014; 5(14):5392-402 [PubMed] Free Access to Full Article Related Publications
Recently we have shown that the transcription factor FOXO1, highly expressed in B cells, is downregulated in classical Hodgkin lymphoma (cHL). As primary mediastinal B cell lymphoma (PMBL) has similarities with the cHL transcription program we investigated FOXO1 expression in this entity. By using immunohistochemistry we found that FOXO1 was absent or expressed at low levels in 19 of 20 primary PMBL cases. PMBL cell lines reproduce the low FOXO1 expression observed in primary cases. By analyzing gene expression profiling data we found that FOXO1 expression inversely correlated with JAK2 in PMBL cases. Targeting JAK2 activity by the small molecular weight inhibitor TG101348 resulted in upregulation of FOXO1 mRNA and protein expression in MedB-1 and U2940 cell lines, and the MYC inhibitor 10058-F4 increased FOXO1 mRNA in MedB-1 cells. Moreover, in MedB-1 cells FOXO1 expression was strongly upregulated by the inhibitor of DNA methylation 5-aza-2-deoxycytidine and by the histone deacetylase inhibitor trichostatin A. Since FOXO1 promoter was unmethylated, this effect is most likely indirect. FOXO1 activation in the FOXO1-negative Med-B1 cell line led to growth arrest and apoptosis, which was accompanied by repression of MYC and BCL2L1/BCLxL. Thus, FOXO1 repression might contribute to the oncogenic program and phenotype of PMBL.

Bergantin E, Quarta C, Nanni C, et al.
Sulforaphane induces apoptosis in rhabdomyosarcoma and restores TRAIL-sensitivity in the aggressive alveolar subtype leading to tumor elimination in mice.
Cancer Biol Ther. 2014; 15(9):1219-25 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Rhadbomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and is subdivided in the embryonal (ERMS) and alveolar (ARMS) subtypes, the latter being associated with the worst prognosis. We report that sulforaphane (SFN), a broccoli-derived anticancer isothiocyanate, causes dose- and time-dependent growth inhibition and apoptosis in both ERMS and ARMS cells. In ARMS, SFN induced the modulation of expression of crucial genes and proteins: mRNA and protein levels of PAX3-FKHR, MYCN, and MET decreased, while those of p21 and TRAIL-receptor DR5 (but not DR4) increased. Since DR5 expression increased specifically in ARMS, we treated ARMS cells with TRAIL, SFN, or their combination. While ARMS cells (RH30 and RH4) proved to be TRAIL-resistant, SFN restored their sensitivity to TRAIL-induced cell-growth inhibition, leading to a stronger effect in combination with TRAIL. ARMS cells transfected with siDR5 showed that SFN-induced DR5 acts as a key regulator, being directly related to the TRAIL-induced cell-growth inhibition. The in vivo anti-tumor activity of SFN and TRAIL was evaluated in a xenograft murine model of ARMS through microPET. The results showed that the systemic treatment (3 wk) of mice with SFN or TRAIL as single agents only delayed tumor evolution, while the combined treatment of SFN and TRAIL led to tumor elimination. These findings indicate that SFN triggers the apoptotic pathway in both alveolar and embryonal rhabdomyosarcomas and that combined treatment with SFN and TRAIL might be a promising therapy for the aggressive alveolar subtype.

Tao YF, Xu LX, Lu J, et al.
Metallothionein III (MT3) is a putative tumor suppressor gene that is frequently inactivated in pediatric acute myeloid leukemia by promoter hypermethylation.
J Transl Med. 2014; 12:182 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Acute myeloid leukemia (AML) is the second most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature in various tumors, including AML. Metallothionein III (MT3) is a tumor suppresser reported to show promoter hypermethylated in various cancers. However, the expression and molecular function of MT3 in pediatric AML is unclear.
METHODS: Eleven human leukemia cell lines and 41 pediatric AML samples and 20 NBM/ITP (Norma bone marrow/Idiopathic thrombocytopenic purpura) control samples were analyzed. Transcription levels of MT3 were evaluated by semi-quantitative and real-time PCR. MT3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BSG). The molecular mechanism of MT3 was investigated by apoptosis assays and PCR array analysis.
RESULTS: The MT3 promoter was hypermethylated in leukemia cell lines. More CpG's methylated of MT3 was observed 39.0% pediatric AML samples compared to 10.0% NBM controls. Transcription of MT3 was also significantly decreased in AML samples compared to NBM/ITP controls (P < 0.001); patients with methylated MT3 exhibited lower levels of MT3 expression compared to those with unmethylated MT3 (P = 0.049). After transfection with MT3 lentivirus, proliferation was significantly inhibited in AML cells in a dose-dependent manner (P < 0.05). Annexin V assay showed that apoptosis was significantly upregulated MT3-overexpressing AML cells compared to controls. Real-time PCR array analysis revealed 34 dysregulated genes that may be implicated in MT3 overexpression and apoptosis in AML, including FOXO1.
CONCLUSION: MT3 may be a putative tumor suppressor gene in pediatric AML. Epigenetic inactivation of MT3 via promoter hypermethylation was observed in both AML cell lines and pediatric AML samples. Overexpression of MT3 may inhibit proliferation and induce apoptosis in AML cells. FOXO1 was dysregulated in MT3-overexpressing cells, offering an insight into the mechanism of MT3-induced apoptosis. However, further research is required to determine the underlying molecular details.

Harjes U, Bridges E, McIntyre A, et al.
Fatty acid-binding protein 4, a point of convergence for angiogenic and metabolic signaling pathways in endothelial cells.
J Biol Chem. 2014; 289(33):23168-76 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Fatty acid-binding protein 4 (FABP4) is an adipogenic protein and is implicated in atherosclerosis, insulin resistance, and cancer. In endothelial cells, FABP4 is induced by VEGFA, and inhibition of FABP4 blocks most of the VEGFA effects. We investigated the DLL4-NOTCH-dependent regulation of FABP4 in human umbilical vein endothelial cells by gene/protein expression and interaction analyses following inhibitor treatment and RNA interference. We found that FABP4 is directly induced by NOTCH. Stimulation of NOTCH signaling with human recombinant DLL4 led to FABP4 induction, independently of VEGFA. FABP4 induction by VEGFA was reduced by blockade of DLL4 binding to NOTCH or inhibition of NOTCH signal transduction. Chromatin immunoprecipitation of the NOTCH intracellular domain showed increased binding to two specific regions in the FABP4 promoter. The induction of FABP4 gene expression was dependent on the transcription factor FOXO1, which was essential for basal expression of FABP4, and FABP4 up-regulation following stimulation of the VEGFA and/or the NOTCH pathway. Thus, we show that the DLL4-NOTCH pathway mediates endothelial FABP4 expression. This indicates that induction of the angiogenesis-restricting DLL4-NOTCH can have pro-angiogenic effects via this pathway. It also provides a link between DLL4-NOTCH and FOXO1-mediated regulation of endothelial gene transcription, and it shows that DLL4-NOTCH is a nodal point in the integration of pro-angiogenic and metabolic signaling in endothelial cells. This may be crucial for angiogenesis in the tumor environment.

Herold T, Metzeler KH, Vosberg S, et al.
Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis.
Blood. 2014; 124(8):1304-11 [PubMed] Related Publications
In acute myeloid leukemia (AML), isolated trisomy 13 (AML+13) is a rare chromosomal abnormality whose prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML+13 patients enrolled in the German AMLCG-1999 and SAL trials and performed exome sequencing, targeted candidate gene sequencing and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML+13 patients were inferior compared to other ELN Intermediate-II patients (n=855) (median RFS, 7.8 vs 14.1 months, P = .006; median OS 9.3 vs. 14.8 months, P = .004). Besides the known high frequency of RUNX1 mutations (75%), we identified mutations in spliceosome components in 88%, including SRSF2 codon 95 mutations in 81%. Recurring mutations were detected in ASXL1 (44%) and BCOR (25%). Two patients carried mutations in CEBPZ, suggesting that CEBPZ is a novel recurrently mutated gene in AML. Gene expression analysis revealed a homogeneous expression profile including upregulation of FOXO1 and FLT3 and downregulation of SPRY2. This is the most comprehensive clinical and biological characterization of AML+13 to date, and reveals a striking clustering of lesions in a few genes, defining AML+13 as a genetically homogeneous subgroup with alterations in a few critical cellular pathways. Clinicaltrials.gov identifiers: AMLCG-1999: NCT00266136; AML96: NCT00180115; AML2003: NCT00180102; and AML60+: NCT00893373.

Wang X, Lin C, Zhao X, et al.
Acylglycerol kinase promotes cell proliferation and tumorigenicity in breast cancer via suppression of the FOXO1 transcription factor.
Mol Cancer. 2014; 13:106 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Acylglycerol kinase (AGK) is reported to be overexpressed in multiple cancers. The clinical significance and biological role of AGK in breast cancer, however, remain to be established.
METHODS: AGK expression in breast cancer cell lines, paired patient tissues were determined using immunoblotting and Real-time PCR. 203 human breast cancer tissue samples were analyzed by immunochemistry (IHC) to investigate the relationship between AGK expression and the clinicopathological features of breast cancer. Functional assays, such as colony formation, anchorage-independent growth and BrdU assay, and a xenograft tumor model were used to determine the oncogenic role of AGK in human breast cancer progression. The effect of AGK on FOXO1 transactivity was further investigated using the luciferase reporter assays, and by detection of the FOXO1 downstream genes.
RESULTS: Herein, we report that AGK was markedly overexpressed in breast cancer cells and clinical tissues. Immunohistochemical analysis showed that the expression of AGK significantly correlated with patients' clinicopathologic characteristics, including clinical stage and tumor-nodule-metastasis (TNM) classification. Breast cancer patients with higher levels of AGK expression had shorter overall survival compared to patients with lower AGK levels. We gained valuable insights into the mechanism of AGK expression in breast cancer cells by demonstrating that overexpressing AGK significantly enhanced, whereas silencing endogenous AGK inhibited, the proliferation and tumorigenicity of breast cancer cells both in vitro and in vivo. Furthermore, overexpression of AGK enhanced G1-S phase transition in breast cancer cells, which was associated with activation of AKT, suppression of FOXO1 transactivity, downregulation of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 and upregulation of the cell cycle regulator cyclin D1.
CONCLUSIONS: Taken together, these findings provide new evidence that AGK plays an important role in promoting proliferation and tumorigenesis in human breast cancer and may serve as a novel prognostic biomarker and therapeutic target in this disease.

Zhao SF, Zhang X, Zhang XJ, et al.
Induction of microRNA-9 mediates cytotoxicity of curcumin against SKOV3 ovarian cancer cells.
Asian Pac J Cancer Prev. 2014; 15(8):3363-8 [PubMed] Related Publications
BACKGROUND: Curcumin, a phenolic compound extracted from the rhizomes of Curcuma longa, has shown cytotoxic effects against a variety of cancers. The aim of this study was to identify potential microRNA (miRNA) mediators of the anticancer effects of curcumin in ovarian cancer cells.
MATERIALS AND METHODS: SKOV3 ovarian cancer cells were treated with curcumin (10-60 μM) and miR-9 expression, cell proliferation, and apoptosis were assessed. The effects of miR-9 depletion on curcumin-mediated growth suppression were also examined. Phosphorylation of Akt and forkhead box protein O1 (FOXO1) was measured in cells with miR-9 overexpression or curcumin treatment.
RESULTS: Curcumin caused a significant and dose-dependent increase of miR-9 expression in SKOV3 cells, while significantly impeding cell proliferation and stimulating apoptosis. Depletion of miR-9 significantly (p<0.05) attenuated the growth-suppressive effects of curcumin on SKOV3 cells, coupled with reduced percentages of apoptotic cells. In contrast, overexpression of miR-9 significantly enhanced the cleavage of caspase-3 and poly(ADP-ribose) polymerase and promoted apoptotic death in SKOV3 cells. Western blot analysis showed that both miR-9 overexpression and curcumin similarly caused a significant (p<0.05) decline in the phosphorylation of Akt and FOXO1, compared to untreated cells.
CONCLUSIONS: The present study provided evidence that curcumin exerts its cytotoxic effects against SKOV3 ovarian cancer cells largely through upregulation of miR-9 and subsequent modulation of Akt/FOXO1 axis. Further studies are needed to identify direct targets of miR-9 that mediate the anticancer effects of curcumin in ovarian cancer cells.

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