Gene Summary

Gene:FOXO1; forkhead box O1
Aliases: FKH1, FKHR, FOXO1A
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, HGNC, Ensembl, GeneCard, Gene
Protein:forkhead box protein O1
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (10)

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

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)

Freire PP, Fernandez GJ, Cury SS, et al.
The Pathway to Cancer Cachexia: MicroRNA-Regulated Networks in Muscle Wasting Based on Integrative Meta-Analysis.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Cancer cachexia is a multifactorial syndrome that leads to significant weight loss. Cachexia affects 50%-80% of cancer patients, depending on the tumor type, and is associated with 20%-40% of cancer patient deaths. Besides the efforts to identify molecular mechanisms of skeletal muscle atrophy-a key feature in cancer cachexia-no effective therapy for the syndrome is currently available. MicroRNAs are regulators of gene expression, with therapeutic potential in several muscle wasting disorders. We performed a meta-analysis of previously published gene expression data to reveal new potential microRNA-mRNA networks associated with muscle atrophy in cancer cachexia. We retrieved 52 differentially expressed genes in nine studies of muscle tissue from patients and rodent models of cancer cachexia. Next, we predicted microRNAs targeting these differentially expressed genes. We also include global microRNA expression data surveyed in atrophying skeletal muscles from previous studies as background information. We identified deregulated genes involved in the regulation of apoptosis, muscle hypertrophy, catabolism, and acute phase response. We further predicted new microRNA-mRNA interactions, such as miR-27a/

Jiang M, Chen Y, Deng L, et al.
Upregulation of
DNA Cell Biol. 2019; 38(5):476-484 [PubMed] Related Publications
Recently, sperm-associated antigen 6 (

Renzi S, Langenberg-Ververgaert K, Fuligni F, et al.
Aggressive embryonal rhabdomyosarcoma in a 3-month-old boy: A clinical and molecular analysis.
Pediatr Hematol Oncol. 2018 Oct - Nov; 35(7-8):407-414 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) represents the most common soft tissue sarcoma in the pediatric age group. While RMS has been traditionally classified on the basis of its histological appearance (with embryonal and alveolar being most common), it is now clear that the PAX-FOXO1 fusion product drives prognosis. We report here a case of pelvic embryonal RMS in a 3-month-old male who was subsequently found to have developed brain metastases during the course of chemotherapy. Cytogenetic analysis of the brain metastases at the time of autopsy as well as next-generation sequencing analysis revealed a reciprocal translocation involving the SH3 domain containing ring finger 3 gene (SH3RF3, on chromosome 2q13) and the Lipase C gene (LIPC, on chromosome 15q21.3). Due to the poor quality of the pretreatment and postresection samples, cytogenetics and NGS analysis looking for the presence of this balanced translocation in these specimens could not be performed. To the authors' knowledge, this translocation has never been described in RMS. Further studies are needed to determine the biological and clinical implications of this novel translocation.

Kawamura A, Kawamura T, Riddell M, et al.
Regulation of programmed cell death ligand 1 expression by atypical protein kinase C lambda/iota in cutaneous angiosarcoma.
Cancer Sci. 2019; 110(5):1780-1789 [PubMed] Free Access to Full Article Related Publications
The expression of immune checkpoint proteins such as programmed cell death protein 1 (PD-1) and its ligand (PD-L1) has been shown to correlate with patient prognosis in many malignant cancers. The expression of PD-L1 is controlled by c-Myc; however, further upstream regulation of PD-L1 expression is largely unknown. We have previously shown that atypical protein kinase C lambda/iota (aPKCλ) phosphorylates the Forkhead box protein O1 (FoxO1) transcription factor at Ser218 to suppress its DNA-binding ability, thereby regulating c-Myc expression and controlling physiologic and pathologic endothelial proliferation. The presence of phosphorylation of FoxO1 at Ser218 (pSer218 FoxO1) in cutaneous angiosarcoma (CAS) strongly correlates with poor patient prognosis. Here, we reported that patients with PD-L1

Chen YC, Liu YC, El-Shazly M, et al.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
Reported cases of breast cancer have skyrocketed in the last decades with recent advances in examination techniques. Brest cancer has become the second leading cause of mortality among women worldwide, urging the scientific community to develop or find new drugs from natural sources with potent activity and a reasonable safety profile to tackle this ailment.

Liu H, Ni Z, Shi L, et al.
MiR-486-5p inhibits the proliferation of leukemia cells and induces apoptosis through targeting FOXO1.
Mol Cell Probes. 2019; 44:37-43 [PubMed] Related Publications
AIM: Studies have reported that micro (miR)-486-5p plays a crucial part in the progression of leukemia, however, to the best of our knowledge, few studies have been conducted on its mechanism in leukemia. In this study, the mechanism of miR-486-5p in leukemia cells was pointed out and its possible target genes were analyzed for the purpose of providing new therapeutic strategies for treating leukemia patients.
METHODS: MiRNA expression of Leukemia cells (K562, Kasumi-1, and THP-1) and primary leukocytes was detected by Real-time Quantitative polymerase chain reaction(qPCR). The activity of the cells was assessed using the Cell Counting Kit-8 (CCK-8). Apoptotic cells were analyzed by a flow cytometer (FCM). Caspase-3 activation in leukemia cells was determined by Western blot. Targetscan 7.2 was used to predict the potential targets of miR-486-5p and further confirmed by dual-luciferase reporter assay.
RESULT: miR-486-5p was significantly down-regulated in leukemia cells. The over-expression of miR-486-5p notably increased the apoptosis and caspase-3 activity in leukemia cells. There was a predicted interaction site for miR-486-5p in the FOXO1 3'-UTR. Furthermore, this study showed that FOXO1 was significantly up-regulated in leukemia cells, the growth of which was depressed by the up-regulation of miR-486-5p.
CONCLUSION: miR-486-5p may inhibit the proliferation of leukemia cells and induce apoptosis through targeting FOXO1.

Zhang LY, Chen Y, Jia J, et al.
MiR-27a promotes EMT in ovarian cancer through active Wnt/𝜷-catenin signalling by targeting FOXO1.
Cancer Biomark. 2019; 24(1):31-42 [PubMed] Related Publications
BACKGROUND: Ovarian cancer (OC) is the fifth most common type of cancer in women worldwide. MiR-27a plays an important role in the development of ovarian cancer. However, the exact function and molecular mechanism of miR-27a in epithelial-mesenchymal transition (EMT) has not been thoroughly elucidated to date.
METHODS: Quantitative real-time PCR (qRT-PCR) was used to determine the expression of miR-27a and FOXO1 mRNA in ovarian tissues and cells. The function of miR-27a in ovarian cancer was investigated through overexpression and knockdown of miR-27a in vitro. Wound healing and Transwell assays were performed to evaluate the migration and invasive capacity of the cells. A luciferase reporter assay was conducted to confirm the interaction between miR-27a and FOXO1. Western blotting was used to evaluate FOXO1, EMT and Wnt/β-catenin relative protein expression.
RESULTS: In our study, we found that the mRNA expression level of miR-27a was significantly higher in ovarian cancer tissues and in HO8910 and OV90 cells. Functional experiments showed that miR-27a overexpression potentiated the migration and invasion of HO8910 and OV90 cells, while miR-27a inhibition reduced the cells' migration and invasion. Moreover, miR-27a upregulated the expression of mesenchymal cell markers and downregulated the expression of epithelial cell markers, which were restored via silencing of miR-27a expression. Subsequently, miR-27a was found to directly target and suppress the expression of FOXO1. Finally, we demonstrated that miR-27a promoted the progression of ovarian cancer cells and induced the process of EMT via the Wnt/β-catenin signalling pathway through inhibition of FOXO1.
CONCLUSIONS: Taken together, these results indicate that targeting miR-27a and FOXO1 could represent a strategy for anticancer therapy in ovarian cancer.

Riddell M, Nakayama A, Hikita T, et al.
aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability.
Nat Commun. 2018; 9(1):5357 [PubMed] Free Access to Full Article Related Publications
Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C lambda/iota (aPKCλ) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKCλ impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKCλ phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKCλ controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a potential therapeutic strategy for treatment of malignant cancers, like angiosarcoma.

Chae YC, Kim JY, Park JW, et al.
FOXO1 degradation via G9a-mediated methylation promotes cell proliferation in colon cancer.
Nucleic Acids Res. 2019; 47(4):1692-1705 [PubMed] Free Access to Full Article Related Publications
Posttranslational modifications of the Forkhead family transcription factor, FOXO1, have been known to have important regulatory implications in its diverse activities. Several types of modifications of FOXO1, including acetylation, phosphorylation, and ubiquitination, have been reported. However, lysine methylation of FOXO1 has not yet been identified. Here, we reported that FOXO1 is methylated by G9a at K273 residue in vitro and in vivo. Methylation of FOXO1 by G9a increased interaction between FOXO1 and a specific E3 ligase, SKP2, and decreased FOXO1 protein stability. In addition, G9a expression was increased by insulin and resulted in insulin-mediated FOXO1 degradation by K273 methylation. Tissue array analysis indicated that G9a was overexpressed and FOXO1 levels decreased in human colon cancer. Cell proliferation assays revealed that G9a-mediated FOXO1 methylation increased colon cancer cell proliferation. Fluorescence-activated cell sorting (FACS) analysis indicated that apoptosis rates were higher in the presence of FOXO1 than in FOXO1 knock-out cells. Furthermore, we found that G9a protein levels were elevated and FOXO1 protein levels were decreased in human colon cancer patients tissue samples. Here, we report that G9a specific inhibitor, BIX-01294, can regulate cell proliferation and apoptosis by inhibiting G9a-mediated FOXO1 methylation.

Duan S, Huang W, Liu X, et al.
IMPDH2 promotes colorectal cancer progression through activation of the PI3K/AKT/mTOR and PI3K/AKT/FOXO1 signaling pathways.
J Exp Clin Cancer Res. 2018; 37(1):304 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Inosine 5'-monophosphate dehydrogenase type II (IMPDH2) was originally identified as an oncogene in several human cancers. However, the clinical significance and biological role of IMPDH2 remain poorly understood in colorectal cancer (CRC).
METHODS: Quantitative real-time polymerase chain reaction (qPCR), western blotting analysis, the Cancer Genome Atlas (TCGA) data mining and immunohistochemistry were employed to examine IMPDH2 expression in CRC cell lines and tissues. A series of in-vivo and in-vitro assays were performed to demonstrate the function of IMPDH2 and its possible mechanisms in CRC.
RESULTS: IMPDH2 was upregulated in CRC cells and tissues at both mRNA and protein level. High IMPDH2 expression was closely associated with T stage, lymph node state, distant metastasis, lymphovascular invasion and clinical stage, and significantly correlated with poor survival of CRC patients. Further study revealed that overexpression of IMPDH2 significantly promoted the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of CRC cells in vitro and accelerated xenograft tumour growth in nude mice. On the contrary, knockdown of IMPDH2 achieved the opposite effect. Gene set enrichment analysis (GSEA) showed that the gene set related to cell cycle was linked to upregulation of IMPDH2 expression. Our study verified that overexpressing IMPDH2 could promote G1/S phase cell cycle transition through activation of PI3K/AKT/mTOR and PI3K/AKT/FOXO1 pathways and facilitate cell invasion, migration and EMT by regulating PI3K/AKT/mTOR pathway.
CONCLUSIONS: These results suggest that IMPDH2 plays an important role in the development and progression of human CRC and may serve as a novel prognostic biomarker and therapeutic target for CRC.

Du X, de Almeida P, Manieri N, et al.
CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription factor FOXO1.
Proc Natl Acad Sci U S A. 2018; 115(50):E11731-E11740 [PubMed] Free Access to Full Article Related Publications
Natural killer (NK) cell recognition of tumor cells is mediated through activating receptors such as CD226, with suppression of effector functions often controlled by negative regulatory transcription factors such as FOXO1. Here we show that CD226 regulation of NK cell cytotoxicity is facilitated through inactivation of FOXO1. Gene-expression analysis of NK cells isolated from syngeneic tumors grown in wild-type or CD226-deficient mice revealed dysregulated expression of FOXO1-regulated genes in the absence of CD226. In vitro cytotoxicity and stimulation assays demonstrated that CD226 is required for optimal killing of tumor target cells, with engagement of its ligand CD155 resulting in phosphorylation of FOXO1. CD226 deficiency or anti-CD226 antibody blockade impaired cytotoxicity with concomitant compromised inactivation of FOXO1. Furthermore, inhibitors of FOXO1 phosphorylation abrogated CD226-mediated signaling and effector responses. These results define a pathway by which CD226 exerts control of NK cell responses against tumors.

Fukuoka K, Kanemura Y, Shofuda T, et al.
Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors.
Acta Neuropathol Commun. 2018; 6(1):134 [PubMed] Free Access to Full Article Related Publications
Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.

Gerber MH, Underwood PW, Judge SM, et al.
Local and Systemic Cytokine Profiling for Pancreatic Ductal Adenocarcinoma to Study Cancer Cachexia in an Era of Precision Medicine.
Int J Mol Sci. 2018; 19(12) [PubMed] Free Access to Full Article Related Publications
Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed. Patient demographics, operative factors, oncologic factors, and perioperative data were collected for the two patients in the patient derived xenograft (PDX) model. Human pancreatic cancer PDX were created by implanting fresh surgical pancreatic cancer tissues directly into immunodeficient mice. At PDX end point, mouse tumor, spleen and muscle tissues were collected and weighed, muscle atrophy related gene expression measured, and tumor and splenic soluble proteins were analyzed. PDX models were created from surgically resected patients who presented with different degrees of cachexia. Tumor free body weight and triceps surae weight differed significantly between the PDX models and control (P < 0.05). Both PDX groups had increased atrophy related gene expression in muscle compared to control (FoxO1, Socs3, STAT3, Acvr2b, Atrogin-1, MuRF1; P < 0.05). Significant differences were noted in splenic soluble protein concentrations in 14 of 15 detected proteins in tumor bearing mice when compared to controls. Eight splenic soluble proteins were significantly different between PDX groups (P < 0.05). Tumor soluble proteins were significantly different between the two PDX groups in 15 of 24 detected proteins (P < 0.05). PDX models preserve the cachectic heterogeneity found in patients and are associated with unique cytokine profiles in both the spleen and tumor between different PDX. These data support the use of PDX as a strategy to study soluble cachexia protein markers and also further efforts to elucidate which cytokines are most related to cachexia in order to provide potential targets for immunotherapy.

Zeng CX, Fu SB, Feng WS, et al.
TCF19 enhances cell proliferation in hepatocellular carcinoma by activating the ATK/FOXO1 signaling pathway.
Neoplasma. 2019; 66(1):46-53 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies because of its complexity, high metastasis, recurrence and limited treatment options. Reports state that transcription factor 19 (TCF19) is related to the susceptibility to chronic HBV infection and that it strongly increases the risk of HCC occurrence, but its molecular mechanisms remain unknown. This study analyzed the datasets and confirmed that TCF19 is significantly increased in HCC cell lines and tissues. MTT and colony formation assay revealed that TCF19 over-expression enhances cell proliferation and tumorigenesis. Flow cytometry assay then determined that TCF over-expression helps HCC cell G1/S phase transition, and further research showed that TCF19 up-regulation inhibits p57Kip2, p21Cip1 and p27Kip1 cell cycle suppressors, enhances the expression of cyclin D1 expression and simulates retinoblastoma (Rb), FOXO1 and AKT phosphorylation. In addition, AKT and FOXO1 inhibitors suppress the TCF19 effect on cell proliferation. This demonstrates that AKT/FOXO1 signaling is essential for TCF19 influence on HCC progression, and our combined results suggest that crucial links between TCF19 and HCC can provide a novel target for hepatocellular carcinoma treatment.

Nguyen TH, Barr FG
Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma.
Molecules. 2018; 23(11) [PubMed] Free Access to Full Article Related Publications
Rhabdomyosarcoma (RMS) is a family of soft tissue cancers that are related to the skeletal muscle lineage and predominantly occur in children and young adults. A specific chromosomal translocation t(2;13)(q35;q14) that gives rise to the chimeric oncogenic transcription factor PAX3-FOXO1 has been identified as a hallmark of the aggressive alveolar subtype of RMS. PAX3-FOXO1 cooperates with additional molecular changes to promote oncogenic transformation and tumorigenesis in various human and murine models. Its expression is generally restricted to RMS tumor cells, thus providing a very specific target for therapeutic approaches for these RMS tumors. In this article, we review the recent understanding of PAX3-FOXO1 as a transcription factor in the pathogenesis of this cancer and discuss recent developments to target this oncoprotein for treatment of RMS.

Devan J, Janikova A, Mraz M
New concepts in follicular lymphoma biology: From BCL2 to epigenetic regulators and non-coding RNAs.
Semin Oncol. 2018; 45(5-6):291-302 [PubMed] Related Publications
The molecular pathogenesis of follicular lymphoma (FL) was partially revealed 3 decades ago, with the discovery of the translocation that brings BCL2 under the influence of immunoglobulin heavy chain enhancers in a vast majority of cases. Despite the importance of this seminal observation, it has become increasingly clear that additional genetic alterations need to occur to trigger neoplastic transformation and disease progression. The evolution of FL involves developmental arrest and disruption of the normal function of one or more of epigenetic regulators including KMT2D/MLL2, EZH2, CBP/CREBBP, p300/EP300, and HIST1H1 in >95% of cases. B-cells "arrested" in germinal centers acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT, TLR, mTOR, NF-κB, JAK/STAT, MAPK, CD40/CD40L, chemokine, and interleukin signaling. Additionally, most cases of FL do not result from linear accumulation of genomic aberrations, but rather evolve from a common progenitor cell population by diverse evolution, creating multiple FL subclones in one patient. Moreover, one of the subclones might acquire a combination of aberrations involving genes controlling cell survival and proliferation including MDM2, CDKN2A/B, BCL6, MYC, TP53, β2M, FOXO1, MYD88, STAT3, or miR-17-92, and this can lead to the transformation of an initially indolent FL to an aggressive lymphoma (2%-3% risk per year). The complexity of the disease is also underscored by the importance of its interactions with the microenvironment that can substantially influence disease development and prognosis. Interpreting individual aberrations in relation to their impact on normal processes, their frequency, position in the disease evolution, and the consequences of their (co)occurrence, are the basis for understanding FL pathogenesis. This is necessary for the identification of patients with risk of early progression or transformation, for the development of novel targeted therapies, and for personalized treatment approaches. In this review, we summarize recent knowledge of molecular pathways and microenvironmental components involved in FL biology, and discuss them in the context of physiological B-cell development, FL evolution, and targeted therapies.

Kabrani E, Chu VT, Tasouri E, et al.
Nuclear FOXO1 promotes lymphomagenesis in germinal center B cells.
Blood. 2018; 132(25):2670-2683 [PubMed] Related Publications
Forkhead box class O1 (FOXO1) acts as a tumor suppressor in solid tumors. The oncogenic phosphoinositide-3-kinase (PI3K) pathway suppresses FOXO1 transcriptional activity by enforcing its nuclear exclusion upon AKT-mediated phosphorylation. We show here abundant nuclear expression of FOXO1 in Burkitt lymphoma (BL), a germinal center (GC) B-cell-derived lymphoma whose pathogenesis is linked to PI3K activation. Recurrent FOXO1 mutations, which prevent AKT targeting and lock the transcription factor in the nucleus, are used by BL to circumvent mutual exclusivity between PI3K and FOXO1 activation. Using genome editing in human and mouse lymphomas in which MYC and PI3K cooperate synergistically in tumor development, we demonstrate proproliferative and antiapoptotic activity of FOXO1 in BL and identify its nuclear localization as an oncogenic event in GC B-cell-derived lymphomagenesis.

Chang Y, Zhou C, Fan L, et al.
Upregulation of microRNA‑300 induces the proliferation of liver cancer by downregulating transcription factor FOXO1.
Oncol Rep. 2018; 40(6):3561-3572 [PubMed] Related Publications
In the present study, we investigated whether miRNA‑300 (miR‑300) is an oncogene in human liver cancer and sought to determine the mechanism underlying its activity. We also investigated the effect of miRNA‑300 on the growth in liver cancer. To identify its target molecule, we performed luciferase assays. The downstream signaling pathway was detected by immunohistochemical (IHC) analysis in human HCC tissues, and the protein levels of AKT, 4E‑BP1, S6K1, SNAIL and MMP2 were determined using western blotting. miR‑300 levels were higher in patients with high‑stage HCC, and miR‑300 promoted cell growth both in vitro and in vivo. miRNA‑300 inhibited the luciferase activity of FOXO1 by targeting its 3'‑untranslated region (UTR), and overexpression of miR‑300 upregulated the protein levels of phospho‑AKT, phospho‑4E‑BP1, phospho‑S6K1, SNAIL and MMP2. These data revealed that miRNA‑300 functions as an oncogene in liver cancer by inhibiting FOXO1 and interacting with the AKT/mTOR signaling pathway.

Tan Y, Wang L, Du Y, et al.
Inhibition of BRD4 suppresses tumor growth in prostate cancer via the enhancement of FOXO1 expression.
Int J Oncol. 2018; 53(6):2503-2517 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is a malignant tumor with a high incidence in males. Localized tumors can be treated via surgery or radiation; however, it remains difficult to prevent disease progression. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader protein that binds to acetylated lysine on histones and has been reported to serve critical roles in numerous types of cancers. In the present study, it was demonstrated that BRD4 expression levels were significantly increased in cancerous prostate tissue specimens and cells, which were associated with clinical stage and metastasis. In addition, the present study reported that inhibition of BRD4 via short hairpin RNA or JQ1 (a bromodomain inhibitor) decreased PCa cell proliferation, induced G0/G1 cell cycle arrest and apoptosis, mitigated cell invasion and migration in vitro, and impaired tumor growth in vivo. Mechanistically, BRD4 inhibition-induced suppression of cell cycle progression was associated with the upregulation of p21 and cyclin D1. c-Myc and B-cell lymphoma-2 (Bcl-2), important genes responsible for cell cycle regulation and anti-apoptotic functions, were downregulated in response to BRD4 inhibition. Furthermore, the present study revealed that c-Myc expression was negatively regulated by p21, and that the induction of p21 via BRD4 inhibition was mediated by forkhead box protein O1 (FOXO1), rather than p53. In summary, the results of the present study suggested that the aberrant expression of BRD4 in PCa may induce carcinogenesis. In addition, a mechanism by which BRD4 inhibition suppresses cell proliferation via the regulation of FOXO1-p21-Myc signaling was proposed in the present study, which may contribute to the development of novel therapeutic approaches in the management of PCa.

Chen X, Luo X, Cheng Y
Trifluoperazine prevents FOXO1 nuclear excretion and reverses doxorubicin-resistance in the SHG44/DOX drug-resistant glioma cell line.
Int J Mol Med. 2018; 42(6):3300-3308 [PubMed] Free Access to Full Article Related Publications
As a tumor suppressor, Forkhead box O1 (FOXO1) is located in the nucleus where it regulates gene expression and inhibits tumor progression. However, the antitumor effects of FOXO1 are attenuated in several tumors due to its translocation from the nucleus to the cytoplasm. Trifluoperazine (TFP) is able to reverse tumor drug resistance by inhibiting multidrug resistance (MDR), however, the detailed molecular mechanisms by which this occurs remain to be fully elucidated. In the present study, the doxorubicin (DOX)‑resistant SHG44/DOX glioma cell line was established. The results showed that TFP promoted DOX‑induced cytotoxicity, cell cycle arrest and early apoptosis using a Cell Counting Kit‑8 and flow cytometry. In vivo experiments also demonstrated that DOX combined with TFP reduced tumor volumes and proliferation indices, and led to higher protein levels of FOXO1. In addition, TFP inhibited the nuclear exclusion of FOXO1, contributing toward the downregulation of MDR genes and an increase in intracellular DOX concentrations by reverse transcription‑quantitative polymerase chain reaction, western blot analysis, immunofluorescence and spectrophotometer analysis. Therefore, TFP may inhibit DOX resistance by stimulating FOXO1 nuclear translocation and suppressing MDF genes in SHG44/DOX cells, contributing to promising clinical prospects for tumor chemotherapy.

Nozhat Z, Mohammadi-Yeganeh S, Azizi F, et al.
Effects of metformin on the PI3K/AKT/FOXO1 pathway in anaplastic thyroid Cancer cell lines.
Daru. 2018; 26(2):93-103 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUND: The PI3K/AKT/FOXO signaling pathway plays an important role in the survival, proliferation and apoptosis of tumor cells. The aim of the present study was to explore whether metformin could affect insulin-promoting cell growth by regulation of this pathway.
MATERIAL AND METHODS: Anaplastic thyroid cancer cells were treated with 0-60 mM metformin for 24, 48 and 72 h. Cell viability, morphology, apoptosis and migration were investigated by MTT assay, microscopy observation, AnexinV-PI and the wound healing assay, respectively. Expression levels of PI3K, AKT and FOXO1 were detected by RT-qPCR, and proteins phosphorylated levels were determined by ELISA.
RESULTS: Metformin decreased cell viability and migration in a significant time-and dose-dependent manner, and induced apoptosis and morphological changes in the cells. RT-qPCR results showed that expression levels of PI3K, AKT and FOXO1 was inhibited by metformin (P < 0.05). However, there was no significant change in the expression level of AKT following metformin treatment for C643 cell line (P > 0.05). ELISA results showed that metformin treatment had no significant effects on the phosphorylated levels of PI3K, AKT and FOXO1 (P > 0.05).
CONCLUSUION: The downregulation of FOXO1 was intensified by metformin, but no increase in cell viability was observed following FOXO1 downregulation by metformin. However, the exact molecular mechanism of metformin on inhibition of the PI3K/AKT pathway and subsequent decrease in cell viability remains unclear and further studies are required for its clarification.

Al-Zoughbi W, Schauer S, Pichler M, Hoefler G
Early Loss of Forkhead Transcription Factor, O Subgroup, Member 1 Protein in the Development of Pancreatic Ductal Adenocarcinoma.
Pathobiology. 2018; 85(5-6):342-347 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
OBJECTIVES: Forkhead transcription factor, O subgroup, member 1 (FOXO1) is a regulatory protein that plays an essential role in cellular homeostasis. A biological function as a tumor suppressor has been proposed. Here, we examined FOXO1 expression in human pancreatic ductal adenocarcinoma (PDAC) and its precursor lesions.
METHODS: We immunohistochemically labeled tissue samples from 47 patients with PDAC for FOXO1 protein. In addition, we extracted data from the Cancer Genome Atlas and the Cancer Cell Line Encyclopedia and studied a potential association with well-established genetic variants. A publicly available microarray dataset of 102 PDAC samples was used to explore the influence of FOXO1 expression on patients' clinical outcome.
RESULTS: Normal ductal epithelium universally expressed nuclear and cytoplasmic FOXO1. Reduced expression was observed in PanIN lesions and PDAC of all cases. Analysis of several datasets showed that the FOXO1 gene transcript levels do not correlate with KRAS, TP53, SMAD4, or CDKN2A mutation status, but positively correlate with patients' outcomes.
CONCLUSIONS: Loss of FOXO1 protein is identified as an early event during PDAC development and may be independent of the top 4 mutated cancer genes. Because of its strong expression in normal ductal cells, immunohistochemical detection of FOXO1 can function as a valuable test to establish the diagnosis of transformation and malignancy in pancreatic tissues.

Välimäki N, Kuisma H, Pasanen A, et al.
Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability.
Elife. 2018; 7 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by

Wang Z, Ji G, Wu Q, et al.
Integrated microarray meta-analysis identifies miRNA-27a as an oncogene in ovarian cancer by inhibiting FOXO1.
Life Sci. 2018; 210:263-270 [PubMed] Related Publications
AIMS: Survival of ovarian cancer patients is generally poor, partly because most of them are already at an advanced stage when diagnosed. The purpose of this study was to screen prognostic miRNAs for ovarian cancer, and to explore the underlying mechanisms.
MAIN METHODS: Integrated meta-analysis of miRNA microarrays retrieved from public repositories was employed to identify clinically significant miRNAs involved in ovarian cancer. Targets of candidate miRNA were predicted using four online databases, and validated with dual luciferase assay. Loss and gain of function were performed to investigate the role of miR27a in the growth of ovarian cancer cell lines.
KEY FINDINGS: Based on cross-validation results in multiple datasets, we recognized hsa-miR-27a as an oncogenic molecular and a prognostic factor for ovarian cancer patients. Dual luciferase assay indicated tumor suppressor FOXO1 was a direct target of miR-27a. In addition, hsa-miR-27a could stimulate SKOV3 and A2780 cell proliferation and migration by regulating the expression of FOXO1.
SIGNIFICANCE: In summary, our results indicate that miR-27a can promote progression of ovarian cancer by mediating FOXO1. To our knowledge, this is the first study focusing on the role of miR-27a/FOXO1 axis using the microarray meta-analysis in ovarian cancer. Furthermore, inhibiting miR-27a expression may be a new strategy for the treatment of ovarian cancer.

Pennington JD, Welch RJ, Lally SE, et al.
Botryoid Rhabdomyosarcoma of the Conjunctiva in a Young Boy.
Middle East Afr J Ophthalmol. 2018 Apr-Jun; 25(2):111-114 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Primary conjunctival rhabdomyosarcoma (RMS) is a rare entity that can present with or without papillomatous features. A 5-year-old Asian boy was referred for a rapidly growing conjunctival tumor in the superior fornix of the left eye. Surgical excision yielded a 28 mm multilobulated papillomatous specimen that exhibited histopathologic and immunohistochemical features consistent with embryonal (botryoid) RMS. Molecular analysis revealed the absence of the PAX3/FOXO1 fusion gene, indicating favorable prognosis. After surgery, he was promptly treated with systemic chemotherapy and proton beam radiotherapy.

Hsu YL, Chen YJ, Chang WA, et al.
Interaction between Tumor-Associated Dendritic Cells and Colon Cancer Cells Contributes to Tumor Progression via CXCL1.
Int J Mol Sci. 2018; 19(8) [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Crosstalk of a tumor with its microenvironment is a critical factor contributing to cancer development. This study investigates the soluble factors released by tumor-associated dendritic cells (TADCs) responsible for increasing cancer stem cell (CSC) properties, cell mobility, and epithelial-to-mesenchymal transition (EMT). Dendritic cells (DCs) of colon cancer patients were collected for phenotype and CXCL1 expression by flow cytometry and Luminex assays. The transcriptome of CXCL1-treated cancer cells was established by next generation sequencing. Inflammatory chemokine CXCL1, present in large amounts in DCs isolated from colon cancer patients, and SW620-conditioned TADCs, enhance CSC characteristics in cancer, supported by enhanced anchorage-independent growth, CD133 expression and aldehyde dehydrogenase activity. Additionally, CXCL1 increases the metastatic ability of a cancer by enhancing cell migration, matrix metalloproteinase-7 expression and EMT. The enhanced CXCL1 expression in DCs is also noted in mice transplanted with colon cancer cells. Transcriptome analysis of CXCL1-treated SW620 cells indicates that CXCL1 increases potential oncogene expression in colon cancer, including

Andreasen S, Bishop JA, Hellquist H, et al.
Biphenotypic sinonasal sarcoma: demographics, clinicopathological characteristics, molecular features, and prognosis of a recently described entity.
Virchows Arch. 2018; 473(5):615-626 [PubMed] Related Publications
Biphenotypic sinonasal sarcoma (BSNS) is a recently recognized type of sarcoma arising exclusively in the sinonasal tract displaying unique clinical course, histopathology, and genetics. Due to its rarity, only case series and case reports are available. In order to provide an overview of the current understanding of this disease, we present a comprehensive review of the literature and present three previously unreported cases of BSNS. A total of 55 genetically characterized and 41 cases without molecular data were identified in the literature. Two-thirds of patients were female and the peak incidence was in the fifth decade. Fatal outcome was rare (two cases with intracranial extension) and local recurrence occurred in 31.6%, all occurring within 5 years after initial treatment. Histologically, BSNS is highly cellular in the majority of cases and composed of fascicles of spindle cells, with entrapped hyperplastic surface epithelium being a frequent finding. The immunohistochemical profile is characteristic due to the biphasic nature of this lesion, with shared features of both myogenic and neural origin. Rhabdomyoblastic differentiation is apparent in a subset of cases. The most common genetic event is the PAX3-MAML3 fusion (58.6%) but isolated PAX3 rearrangement (19.2%), absence of rearrangements (9.1%), PAX3-FOXO1 (8.1%), PAX3-NCOA1 (4%), and isolated MAML3 rearrangement (2%) have also been reported. In conclusion, the recognition of BSNS is crucial due to its relatively indolent clinical course. A selected immunohistochemical panel and/or molecular confirmation can be used to aid in appropriate diagnosis and consequently in prognostication and to avoid overtreatment with chemotherapy regimens used in its mimics.

Xiong DD, Dang YW, Lin P, et al.
A circRNA-miRNA-mRNA network identification for exploring underlying pathogenesis and therapy strategy of hepatocellular carcinoma.
J Transl Med. 2018; 16(1):220 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUND: Circular RNAs (circRNAs) have received increasing attention in human tumor research. However, there are still a large number of unknown circRNAs that need to be deciphered. The aim of this study is to unearth novel circRNAs as well as their action mechanisms in hepatocellular carcinoma (HCC).
METHODS: A combinative strategy of big data mining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and computational biology was employed to dig HCC-related circRNAs and to explore their potential action mechanisms. A connectivity map (CMap) analysis was conducted to identify potential therapeutic agents for HCC.
RESULTS: Six differently expressed circRNAs were obtained from three Gene Expression Omnibus microarray datasets (GSE78520, GSE94508 and GSE97332) using the RobustRankAggreg method. Following the RT-qPCR corroboration, three circRNAs (hsa_circRNA_102166, hsa_circRNA_100291 and hsa_circRNA_104515) were selected for further analysis. miRNA response elements of the three circRNAs were predicted. Five circRNA-miRNA interactions including two circRNAs (hsa_circRNA_104515 and hsa_circRNA_100291) and five miRNAs (hsa-miR-1303, hsa-miR-142-5p, hsa-miR-877-5p, hsa-miR-583 and hsa-miR-1276) were identified. Then, 1424 target genes of the above five miRNAs and 3278 differently expressed genes (DEGs) on HCC were collected. By intersecting the miRNA target genes and the DEGs, we acquired 172 overlapped genes. A protein-protein interaction network based on the 172 genes was established, with seven hubgenes (JUN, MYCN, AR, ESR1, FOXO1, IGF1 and CD34) determined from the network. The Gene Oncology, Kyoto Encyclopedia of Genes and Genomes and Reactome enrichment analyses revealed that the seven hubgenes were linked with some cancer-related biological functions and pathways. Additionally, three bioactive chemicals (decitabine, BW-B70C and gefitinib) based on the seven hubgenes were identified as therapeutic options for HCC by the CMap analysis.
CONCLUSIONS: Our study provides a novel insight into the pathogenesis and therapy of HCC from the circRNA-miRNA-mRNA network view.

Qin Y, Li L, Wang F, et al.
Knockdown of Mir-135b Sensitizes Colorectal Cancer Cells to Oxaliplatin-Induced Apoptosis Through Increase of FOXO1.
Cell Physiol Biochem. 2018; 48(4):1628-1637 [PubMed] Related Publications
BACKGROUND/AIMS: Aberrant expression of microRNAs (miRNAs) is found to be responsible for tumorigenesis, cancer development and chemoresistance. Although oxaliplatin is an effective chemotherapeutic drug for treatment of colorectal cancer (CRC), CRC cells can develop some mechanisms to evade oxaliplatin-induced cell death. It is urgent to explore the novel strategies to increase the chemosensitivity of CRC cells.
METHODS: QRT-PCR analysis was performed to detect the expression of miR-135b in CRC patients' serum and CRC cell lines. MTT assays were used to evaluate the effect of anti-miR-135b on oxaliplatin-induced cell death in CRC cell lines. Western blot, flow cytometry and luciferase reporter assays were performed to evaluate the potential mechanism and pathway of anti-miR-135b-promoted apoptosis in oxaliplatin-treated CRC cells.
RESULTS: Significant upregulation of miR-135b was observed in CRC cell lines and CRC patients' serum. Knockdown of miR-135b was found to sensitize colorectal cancer cells to oxaliplatin-induced cytotoxicity. Mechanically, knockdown of miR-135b increased the expression level of FOXO1 in CRC. As the downstream, the increased FOXO1 induced by anti-miR-135b promoted the expression of Bim and Noxa. Since Bim and Noxa act as key pro-apoptotic proteins in mitochondrial apoptosis, anti-miR-135b was able to enhance the oxaliplatin-induced apoptosis dependent on the anti-miR-135b/FOXO1 axis.
CONCLUSIONS: Anti-miR-135b enhanced the anti-tumor effect of oxaliplatin on CRC. Combination with miR-135b antisense nucleotides may represent a novel strategy to sensitize CRC to oxaliplatin-based treatment.

Özdemir İ, Pınarlı FG, Pınarlı FA, et al.
Epigenetic silencing of the tumor suppressor genes SPI1, PRDX2, KLF4, DLEC1, and DAPK1 in childhood and adolescent lymphomas.
Pediatr Hematol Oncol. 2018; 35(2):131-144 [PubMed] Related Publications
The aim of the study was to investigate the expression and methylation status of seven distinctive genes with tumor suppressing properties in childhood and adolescent lymphomas. A total of 96 patients with Hodgkin Lymphoma (HL, n = 41), Non-Hodgkin Lymphoma (NHL, n = 15), and reactive lymphoid hyperplasia (RLH, n = 40, as controls) are included in the research. The expression status of CDKN2A, SPI1, PRDX2, DLEC1, FOXO1, KLF4 and DAPK1 genes were measured with QPCR method after the RNA isolation from paraffin blocks of tumor tissue and cDNA conversion. DNA isolation was performed from samples with low gene expression followed by methylation PCR study specific to promoter regions of these genes. We found that SPI1, PRDX2, DLEC1, KLF4, and DAPK1 genes are significantly less expressed in patient than the control group (p = 0.0001). However, expression of CDKNA2 and FOXO1 genes in the patient and control groups were not statistically different. The methylation ratios of all genes excluding the CDKN2A and FOXO1 were significantly higher in the HL and NHL groups than the controls (p = 0.0001). We showed that SPI1, PRDX2, DLEC1, KLF4 and DAPK1 genes are epigenetically silenced via hypermethylation in the tumor tissues of children with HL and NHL. As CDKN2A gene was not expressed in both patient and control groups, we conclude that it is not specific to malignancy. As FOXO1 gene was similarly expressed in both groups, its relationship with malignancy could not be established. The epigenetically silenced genes may be candidates for biomarkers or therapeutic targets in childhood and adolescent lymphomas.

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