FOXN3

Gene Summary

Gene:FOXN3; forkhead box N3
Aliases: CHES1, PRO1635, C14orf116
Location:14q31.3-q32.11
Summary:This gene is a member of the forkhead/winged helix transcription factor family. Checkpoints are eukaryotic DNA damage-inducible cell cycle arrests at G1 and G2. Checkpoint suppressor 1 suppresses multiple yeast checkpoint mutations including mec1, rad9, rad53 and dun1 by activating a MEC1-independent checkpoint pathway. Alternative splicing is observed at the locus, resulting in distinct isoforms. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:forkhead box protein N3
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.

  • Neoplastic Cell Transformation
  • Cell Division
  • Young Adult
  • Neoplasm Metastasis
  • Wnt Signaling Pathway
  • Reproducibility of Results
  • Up-Regulation
  • Hepatocellular Carcinoma
  • MicroRNAs
  • Zinc Finger E-box Binding Homeobox 2
  • Gene Expression Profiling
  • Signal Transduction
  • Forkhead Transcription Factors
  • Sequence Deletion
  • Cell Cycle Proteins
  • Multiple Endocrine Neoplasia Type 1
  • Cell Movement
  • beta Catenin
  • Messenger RNA
  • Base Sequence
  • Cancer Gene Expression Regulation
  • Biomarkers, Tumor
  • X Chromosome
  • Adolescents
  • Proto-Oncogene Proteins
  • Breast Cancer
  • Pancreatic Cancer
  • Transcription
  • Chromosome 14
  • Homeodomain Proteins
  • Leukemic Gene Expression Regulation
  • Neoplasm Proteins
  • Transfection
  • Tumor Suppressor Gene
  • Transcription Factors
  • Oligonucleotide Array Sequence Analysis
  • Repressor Proteins
  • Cell Proliferation
  • DNA-Binding Proteins
  • Liver Cancer
  • Molecular Sequence Data
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: FOXN3 (cancer-related)

Li J, Yu X, Liu Q, et al.
Screening of important lncRNAs associated with the prognosis of lung adenocarcinoma, based on integrated bioinformatics analysis.
Mol Med Rep. 2019; 19(5):4067-4080 [PubMed] Free Access to Full Article Related Publications
The study aimed to elucidate the mechanisms underlying the occurrence and development of lung adenocarcinoma, and to reveal long non‑coding RNA (lncRNA) prognostic factors to identify patients at high risk of disease recurrence or metastasis. Based on extensive RNA sequencing data and clinical survival prognosis information from patients with lung adenocarcinoma, obtained from The Cancer Genome Atlas and the Gene Expression Omnibus databases, a co‑expression network of lncRNAs with different expression levels was built using weighted correlation network analysis and MetaDE.ES. The prognostic lncRNAs were identified using the Cox proportional hazards model and Kaplan‑Meier survival curves to construct a risk scoring system. The reliability of the system was confirmed in validation datasets. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed on the genes significantly associated with the prognostic lncRNAs using gene set enrichment analysis. A total of 58 and 1,633 differentially expressed lncRNAs and mRNAs were identified, respectively. Considering the module stability, annotation, correlation between modules and clinical factors, and the differential expression levels of lncRNAs, 32 differentially expressed lncRNAs were selected from the brown, red, blue, green and yellow modules for subsequent survival analysis. A signature‑based risk scoring system involving five lncRNAs [DIAPH2 antisense RNA 1, FOXN3 antisense RNA 2, long intergenic non‑protein coding RNA 652, maternally expressed 3 and RHPN1 antisense RNA 1 (head to head)] was developed. The system successfully distinguished between low‑ and high‑risk prognostic samples. System effectiveness was further verified using two independent validation datasets. Further KEGG pathway analysis indicated that the target genes of the five prognostic lncRNAs were associated with a number of cellular processes and signaling pathways, including the cell receptor‑mediated signaling and cell adhesion pathways. A five‑lncRNA signature predicts the prognosis of patients with lung adenocarcinoma. These prognostic lncRNAs may be potential diagnostic markers. The present results may help elucidate the pathogenesis of lung adenocarcinoma.

Han TS, Voon DC, Oshima H, et al.
Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice.
Gastroenterology. 2019; 156(4):1140-1155.e4 [PubMed] Related Publications
BACKGROUND & AIMS: Gastritis is associated with development of stomach cancer, but little is known about changes in microRNA expression patterns during gastric inflammation. Specific changes in gene expression in epithelial cells are difficult to monitor because of the heterogeneity of the tissue. We investigated epithelial cell-specific changes in microRNA expression during gastric inflammation and gastritis-associated carcinogenesis in mice.
METHODS: We used laser microdissection to enrich epithelial cells from K19-C2mE transgenic mice, which spontaneously develop gastritis-associated hyperplasia, and Gan mice, which express activated prostaglandin E2 and Wnt in the gastric mucosa and develop gastric tumors. We measured expression of epithelial cell-enriched microRNAs and used bioinformatics analyses to integrate data from different systems to identify inflammation-associated microRNAs. We validated our findings in gastric tissues from mice and evaluated protein functions in gastric cell lines (SNU-719, SNU-601, SNU-638, AGS, and GIF-14) and knockout mice. Organoids were cultured from gastric corpus tissues of wild-type and miR-135b-knockout C57BL/6 mice. We measured levels of microRNAs in pairs of gastric tumors and nontumor mucosa from 28 patients in Japan.
RESULTS: We found microRNA 135b (miR-135B) to be the most overexpressed microRNA in gastric tissues from K19-C2mE and Gan mice: levels increased during the early stages of gastritis-associated carcinogenesis. Levels of miR-135B were also increased in gastric tumor tissues from gp130
CONCLUSIONS: We found expression of miR-135B to be up-regulated by interleukin L1 signaling in gastric cancer cells and organoids. miR-135B promotes invasiveness and stem-cell features of gastric cancer cells in culture by reducing FOXN3 and RECK messenger RNAs. Levels of these messenger RNA targets, which encode tumor suppressor, are reduced in human gastric tumors.

Lee SH, Singh I, Tisdale S, et al.
Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia.
Nature. 2018; 561(7721):127-131 [PubMed] Free Access to Full Article Related Publications
DNA mutations are known cancer drivers. Here we investigated whether mRNA events that are upregulated in cancer can functionally mimic the outcome of genetic alterations. RNA sequencing or 3'-end sequencing techniques were applied to normal and malignant B cells from 59 patients with chronic lymphocytic leukaemia (CLL)

Perrier ND
From Initial Description by Wermer to Present-Day MEN1: What have We Learned?
World J Surg. 2018; 42(4):1031-1035 [PubMed] Related Publications
INTRODUCTION: Pancreas, parathyroid, and pituitary, are referred to as the "3 Ps" of MEN1. The time has come to move beyond those Ps and begin to discuss (1) prediction, (2) pausing progression, and (3) prevention of MEN1.
METHODS: In preparation for the International Association of Endocrine Surgeons State of the Art address, updates and uncertainties of MEN were reviewed. This included a detailed examination of the MEN1 gene and the library of implicated mutations, exon sequencing databases and cell cycle pathways. Therapeutic options including radiofrequency ablation, systemic therapy, peptide receptor radionuclide therapy, immune checkpoint inhibitor mechanisms and preimplantation genetic testing were described.
RESULTS: Several key points included mutations in exon 2 are suspected of being associated with a higher rate of distant metastases, a higher rate of PNET development, and more aggressive disease. The suggestion that missense mutations involving loss of interaction with CHES1 (associated with DNA repair) correlates with more aggressive disease and is more closely associated with death related to PNET than to death from other causes was mentioned. For advanced NETs, optimism for agents under study include lanreotide, a long-acting somatostatin analog, and everolimus (Afinitor), a mammalian target of rapamycin (mTOR) inhibitor. The NETest shows the potential value of being a multidimensional tumor marker for response to therapy. Preimplantation genetic diagnosis (PGD) is applicable.
CONCLUSION: Adjunct modalities and determination of the effect of therapy for MEN1 is needed. Prediction through early detection of aggressive disease is an idea worth spreading. We are called us to engage with our patients about prevention, the only true cure.

Li W, Zhang Z, Liu X, et al.
The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer.
J Clin Invest. 2017; 127(9):3421-3440 [PubMed] Free Access to Full Article Related Publications
The pathophysiological function of the forkhead transcription factor FOXN3 remains to be explored. Here we report that FOXN3 is a transcriptional repressor that is physically associated with the SIN3A repressor complex in estrogen receptor-positive (ER+) cells. RNA immunoprecipitation-coupled high-throughput sequencing identified that NEAT1, an estrogen-inducible long noncoding RNA, is required for FOXN3 interactions with the SIN3A complex. ChIP-Seq and deep sequencing of RNA genomic targets revealed that the FOXN3-NEAT1-SIN3A complex represses genes including GATA3 that are critically involved in epithelial-to-mesenchymal transition (EMT). We demonstrated that the FOXN3-NEAT1-SIN3A complex promotes EMT and invasion of breast cancer cells in vitro as well as dissemination and metastasis of breast cancer in vivo. Interestingly, the FOXN3-NEAT1-SIN3A complex transrepresses ER itself, forming a negative-feedback loop in transcription regulation. Elevation of both FOXN3 and NEAT1 expression during breast cancer progression corresponded to diminished GATA3 expression, and high levels of FOXN3 and NEAT1 strongly correlated with higher histological grades and poor prognosis. Our experiments uncovered that NEAT1 is a facultative component of the SIN3A complex, shedding light on the mechanistic actions of NEAT1 and the SIN3A complex. Further, our study identified the ERα-NEAT1-FOXN3/NEAT1/SIN3A-GATA3 axis that is implicated in breast cancer metastasis, providing a mechanistic insight into the pathophysiological function of FOXN3.

Nagel S, Pommerenke C, Meyer C, et al.
Identification of a tumor suppressor network in T-cell leukemia.
[PubMed] Related Publications
To identify novel cancer-related genes targeted by copy number alterations, we performed genomic profiling of T-cell acute lymphoblastic leukemia (T-ALL) cell lines. In 3/8, we identified a shared deletion at chromosomal position 2p16.3-p21. Within the minimally deleted region, we recognized several candidate tumor suppressor (TS) genes, including FBXO11 and FOXN2. An additional deletion at chromosome 14q23.2-q32.11 included FOXN3, highlighting this class of FOX genes as potential TS. Quantitative expression analyses of FBXO11, FOXN2, and FOXN3 confirmed reduced transcript levels in the identified cell lines. Moreover, reduced expression of these genes was also observed in about 7% of T-ALL patients, showing their clinical relevance in this malignancy. Bioinformatic analyses revealed concurrent reduction of FOXN2 and/or FOXN3 together with homeobox gene ZHX1. Consistently, experiments demonstrated that both FOXN2 and FOXN3 directly activated transcription of ZHX1. Taken together, we identified novel TS genes forming a regulatory network in T-cell development and leukemogenesis.

Dai Y, Wang M, Wu H, et al.
Loss of FOXN3 in colon cancer activates beta-catenin/TCF signaling and promotes the growth and migration of cancer cells.
Oncotarget. 2017; 8(6):9783-9793 [PubMed] Free Access to Full Article Related Publications
Aberrant activation of beta-catenin/TCF is a hallmark of colon cancer. How the functions of nuclear localized beta-catenin are regulated is not fully understood. Here, it was found that FOXN3 (Forkhead box N3) was down-regulated in colon cancer tissues. Forced expression of FOXN3 inhibited the growth, migration and invasion of colon cancer cells, while knocking down the expression of FOXN3 promoted the growth, migration, invasion and metastasis of colon cancer cells. FOXN3 bind to beta-catenin and inhibited beta-catenin/TCF signaling by blocking the interaction between beta-catenin and TCF4. Taken together, these data demonstrated the suppressive roles of FOXN3 in the progression of colon cancer, and indicated that restoring the functions of FOXN3 would be a novel therapeutic strategy for colon cancer.

Sun J, Li H, Huo Q, et al.
The transcription factor FOXN3 inhibits cell proliferation by downregulating E2F5 expression in hepatocellular carcinoma cells.
Oncotarget. 2016; 7(28):43534-43545 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and the mechanisms underlying the development of HCC remain to be elucidated. Forkhead box N3 (FOXN3) is an important member of the FOX family of transcription factors that plays an essential role in several cancers but has not been investigated in HCC. In this study, we demonstrate that FOXN3 is downregulated in human primary HCC tissues compared with their matched adjacent liver tissues. Functional tests of FOXN3 demonstrated that FOXN3 inhibits the proliferation of HCC cells in vitro and in vivo. Additionally, FOXN3 repressed the mRNA and protein expression of E2F5, a reported potential oncogene, by inhibiting the promoter activity of E2F5. Collectively, our findings indicate that FOXN3 functions as a tumor suppressor in HCC by downregulating the expression of E2F5.

Mudduluru G, Abba M, Batliner J, et al.
A Systematic Approach to Defining the microRNA Landscape in Metastasis.
Cancer Res. 2015; 75(15):3010-9 [PubMed] Related Publications
The microRNA (miRNA) landscape changes during the progression of cancer. We defined a metastasis-associated miRNA landscape using a systematic approach. We profiled and validated miRNA and mRNA expression in a unique series of human colorectal metastasis tissues together with their matched primary tumors and corresponding normal tissues. We identified an exclusive miRNA signature that is differentially expressed in metastases. Three of these miRNAs were identified as key drivers of an EMT-regulating network acting though a number of novel targets. These targets include SIAH1, SETD2, ZEB2, and especially FOXN3, which we demonstrated for the first time as a direct transcriptional suppressor of N-cadherin. The modulation of N-cadherin expression had significant impact on migration, invasion, and metastasis in two different in vivo models. The significant deregulation of the miRNAs defining the network was confirmed in an independent patient set as well as in a database of diverse malignancies derived from more than 6,000 patients. Our data define a novel metastasis-orchestrating network based on systematic hypothesis generation from metastasis tissues.

Robertson E, Perry C, Doherty R, Madhusudan S
Transcriptomic profiling of Forkhead box transcription factors in adult glioblastoma multiforme.
Cancer Genomics Proteomics. 2015 May-Jun; 12(3):103-12 [PubMed] Related Publications
BACKGROUND: The Forkhead box transcription factor (FOX) family plays an essential role in embryogenesis, especially during brain development. Our hypothesis is that de-regulation of FOX genes may contribute to aggressive tumor biology and therapy resistance in patients with glioblastoma multiforme (GBM).
MATERIALS AND METHODS: Univariate and multivariate analyses were performed to evaluate prognostic significance of transcript levels of 31 FOX genes in a test set of GBM patients (n=191) and validated them in The Cancer Genome Atlas (TCGA) cohort comprising of 508 adult cases of GBM. The predictive significance of key FOX genes was investigated in patients who received chemotherapy or radiotherapy.
RESULTS: Low FOXA2 mRNA, low FOXN2 mRNA, low FOXN3 mRNA and high FOXG1 mRNA were associated with poor survival in the test and TCGA validation cohorts. In multivariate analysis, low FOXA2 mRNA, low FOXN2 mRNA, low FOXN3 mRNA and high FOXG1 mRNA remained independently associated with poor survival in the test and TCGA validation cohorts. In patients who received chemotherapy or radiotherapy, low FOXA2 mRNA, low FOXN2 mRNA and high FOXG1 mRNA correlated with adverse outcomes in the TCGA validation cohort.
CONCLUSION: To our knowledge, our data provide the first comprehensive clinical evidence that FOXA2, FOXN2, FOXN3 and FOXG1 are promising biomarkers of GBM and warrant further investigation.

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.

Zhang R, Lee JY, Wang X, et al.
Identification of novel genomic aberrations in AML-M5 in a level of array CGH.
PLoS One. 2014; 9(4):e87637 [PubMed] Free Access to Full Article Related Publications
To assess the possible existence of unbalanced chromosomal abnormalities and delineate the characterization of copy number alterations (CNAs) of acute myeloid leukemia-M5 (AML-M5), R-banding karyotype, oligonucelotide array CGH and FISH were performed in 24 patients with AML-M5. A total of 117 CNAs with size ranging from 0.004 to 146.263 Mb was recognized in 12 of 24 cases, involving all chromosomes other than chromosome 1, 4, X and Y. Cryptic CNAs with size less than 5 Mb accounted for 59.8% of all the CNAs. 12 recurrent chromosomal alterations were mapped. Seven out of them were described in the previous AML studies and five were new candidate AML-M5 associated CNAs, including gains of 3q26.2-qter and 13q31.3 as well as losses of 2q24.2, 8p12 and 14q32. Amplication of 3q26.2-qter was the sole large recurrent chromosomal anomaly and the pathogenic mechanism in AML-M5 was possibly different from the classical recurrent 3q21q26 abnormality in AML. As a tumor suppressor gene, FOXN3, was singled out from the small recurrent CNA of 14q32, however, it is proved that deletion of FOXN3 is a common marker of myeloid leukemia rather than a specific marker for AML-M5 subtype. Moreover, the concurrent amplication of MLL and deletion of CDKN2A were noted and it might be associated with AML-M5. The number of CNA did not show a significant association with clinico-biological parameters and CR number of the 22 patients received chemotherapy. This study provided the evidence that array CGH served as a complementary platform for routine cytogenetic analysis to identify those cryptic alterations in the patients with AML-M5. As a subtype of AML, AML-M5 carries both common recurrent CNAs and unique CNAs, which may harbor novel oncogenes or tumor suppressor genes. Clarifying the role of these genes will contribute to the understanding of leukemogenic network of AML-M5.

Iżykowska K, Zawada M, Nowicka K, et al.
Submicroscopic genomic rearrangements change gene expression in T-cell large granular lymphocyte leukemia.
Eur J Haematol. 2014; 93(2):143-9 [PubMed] Related Publications
OBJECTIVES: To better understand the molecular pathogenesis of T-cell large granular lymphocyte leukemia (T-LGL), we decided to search for those genetic alterations in T-LGL patients and MOTN-1 cell line (established from T-LGL patient) that have an impact on gene expression and as a result can influence cell biology.
METHODS: Multicolor fluorescence in situ hybridization (mFISH) analysis of the MOTN-1 cell line was performed as well as paired-end next-generation sequencing (NGS; Illumina HiSeq2000) of this cell line and one T-LGL patient. In addition, chosen 6q region was characterized in three T-LGL patients using high-resolution comparative genomic hybridization (FT-CGH) and LM-PCR. Gene expression was studied by RNA sequencing (RNAseq; SOLID5500).
RESULTS: Rearrangements were detected within 1p and 2q in MOTN-1 affecting expression of FGR, ZEB2, and CASP8, and within 6q in MOTN-1 and one T-LGL patient affecting MAP3K5 and IFNGR1. Nineteen genes, among them FOXN3, RIN3, AKT1, PPP2R5C, were overexpressed as a result of an amplification in 14q in one T-LGL patient. Two novel fusion transcripts were identified: CASP8-ERBB4 in MOTN-1 and SBF1-PKHD1L1 in T-LGL patient.
CONCLUSIONS: This study showed that submicroscopic genomic rearrangements change gene expression in T-LGL. Several genes involved in rearrangements were previously linked to cancer and survival pattern that characterizes T-LGL cells.

Li Q, Li X, Guo Z, et al.
MicroRNA-574-5p was pivotal for TLR9 signaling enhanced tumor progression via down-regulating checkpoint suppressor 1 in human lung cancer.
PLoS One. 2012; 7(11):e48278 [PubMed] Free Access to Full Article Related Publications
Accumulating data suggested that functional expression of Toll-like receptors (TLRs) in tumor cells was involved in tumor progression. Our previous study demonstrated that TLR9 signaling could enhance the tumor progression of human lung cancer cells in vitro and in vivo. We further showed that miR-574-5p was the mostly up-regulated miRNA in human lung cancer cells under TLR9 signaling by miRNA array analysis. Here we characterized the potential role of miRNA-574-5p in enhanced tumor progression induced by TLR9 signaling in human lung cancer. We confirmed that TLR9 signaling effectively elevated the expression of miR-574-5p in human lung cancer cells. Notably, we found that down-regulation of miRNA-574-5p using miR-574-5p inhibitor in vitro or miR-574-5p sponge in vivo significantly abrogated the enhanced tumor progression induced by TLR9 signaling. Further studies showed that miR-574-5p was an important player associated with enhanced tumor progression of human lung cancer cells. Notably, we identified checkpoint suppressor 1 (Ches1) as the dominant direct target for miRNA-574-5p to confer the TLR9 signaling enhanced tumor progression. We revealed that over-expression of Ches1 significantly inhibited the cell cycle entry of human lung cancer cells. Finally, we revealed that the expression of miR-574-5p was positively correlated with TLR9 and reversely correlated with Ches1 in lung cancer patients. Our findings not only facilitated the further understanding of the crosstalk between miRNAs and TLRs in tumor biology, but also provided novel potential candidates for treatment of cancer.

Chen YJ, Liao CT, Chen PJ, et al.
Downregulation of Ches1 and other novel genes in oral cancer cells chronically exposed to areca nut extract.
Head Neck. 2011; 33(2):257-66 [PubMed] Related Publications
BACKGROUND: This study was undertaken to identify the genes in response to areca nut extract, a potential carcinogen of oral cancer.
METHODS: Two oral cancer sublines chronically treated with areca nut extract were established. Methods such as microarray and immunohistochemistry were used to screen and validate the genes' altered expressions in areca nut extract-sublines or in cancer tissues.
RESULTS: A total of 35 genes were differentially expressed in both sublines. Several functional pathways were significantly altered. Six genes were confirmed over 2-fold of changes, including Ches1. Functional analyses showed that overexpression of Ches1 suppressed cell growth and arrested cells in the G2/M phase. Consistently, this gene has reduced expression in 52% of oral cancer tissues, which was significantly correlated with the areca nut chewing habit of patients (p = .04).
CONCLUSION: We identified 35 candidates and validated 6 genes that may be associated with areca nut-induced oral cancer. Loss of Ches1 may be attributed to areca nut extract-induced oral carcinogenesis.

Markowski J, Oczko-Wojciechowska M, Gierek T, et al.
Gene expression profile analysis in laryngeal cancer by high-density oligonucleotide microarrays.
J Physiol Pharmacol. 2009; 60 Suppl 1:57-63 [PubMed] Related Publications
The assessment of gene expression profile in laryngeal cancer shall allow to implement molecular biology methods in diagnostics, as well as in prognosis of the course of disease. Thus, it may influence the choice of the most optimal decisions in regards to the method of treatment, extent of surgical procedure, or the necessity of adding post-operative radiotherapy. The aim of the project was to analyse the gene expression profile of laryngeal cancer using oligonucleotide microarrays, aiming to derive novel molecular markers for that carcinoma. The study comprised a group of 14 patients (12 males and 2 females) with squamous cell laryngeal carcinoma, diagnosed and surgically treated between 2005 - 2007 in the ENT Department of the Silesian Medical University in Katowice, Poland. RNA was isolated from frozen tissue fragments. To assess gene expression profile, high density oligonucleotide microarrays (Affymetrix U 133 Plus 2.0) were applied, with over 54 thousand probesets for over 47 thousand transcripts. Four genes, previously not assesed in diagnostic context in laryngeal carcinoma, seemed to be valuable markers of that neoplasm. These are: metalloproteinase ADAM12, cycline-dependent kinase 2 - CDK2, kinesine 14 - KIF14, suppressor 1 of checkpoint - CHES1.

Markowski J, Tyszkiewicz T, Jarzab M, et al.
Metal-proteinase ADAM12, kinesin 14 and checkpoint suppressor 1 as new molecular markers of laryngeal carcinoma.
Eur Arch Otorhinolaryngol. 2009; 266(10):1501-7 [PubMed] Related Publications
The assessment of gene expression profile in laryngeal cancer allows implementation of molecular biology methods in diagnostics, as well as in prognosticating the course of disease, thus allowing taking most optimal decisions as regards the method of treatment, scope of surgical procedure, or the necessity of adding complementary radiotherapy. The aim of the project was to analyze the gene expression profile in laryngeal cancer using oligonucleotide microarrays, having in mind searching new molecular markers for that carcinoma. The study comprised a group of 43 patients (38 males and 5 females) suffering from squamous cell laryngeal carcinoma, diagnosed and surgically treated in the years 2005-2007 in the ENT Department of the Silesian Medical University in Katowice, Poland. RNA was isolated from frozen tissue fragments, with the use of columns RNeasy Midi and Mini Kit (Qiagen). For the examination of gene expression profile, oligonucleotide microarrays of high density were used, provided by Affymetrix (U 133 2.0 PLUS) containing over 54,000 probes for over 47,000 transcripts. Four genes previously not examined in that respect in laryngeal carcinoma, occurred to be good markers of the neoplasm. They are: metal-proteinase ADAM12, cyclin-dependent kinase 2-CDK2, kinesin 14-KIF14, suppressor 1 of checkpoint-CHES1. The analysis of gene expression profile allows, in laryngeal carcinoma, to point out to new genes, which in future may become molecular markers of the carcinoma.

Pehlivan D, Gunduz E, Gunduz M, et al.
Loss of heterozygosity at chromosome 14q is associated with poor prognosis in head and neck squamous cell carcinomas.
J Cancer Res Clin Oncol. 2008; 134(12):1267-76 [PubMed] Related Publications
PURPOSE AND METHODS: Loss of heterozygosity (LOH) in a chromosomal location indicates the presence of an inactivated tumor suppressor gene (TSG). Inactivation of TSG has a functional role in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC). Based on the recent evidences of a putative TSG on chromosome 14, we examined LOH on chromosome 14q using eight polymorphic microsatellite markers in 50 cases of HNSCCs.
RESULTS: Three regions were detected to have a high LOH rate which included 14q21.2-22.3 (42.5%), 14q31 (55%), and 14q32.1 (37%). The correlation between LOH and clinicopathological findings was investigated through statistical analyses. A strong correlation was observed between the highest LOH marker and the overall and disease-free survival.
CONCLUSIONS: The results suggest that the distal part of chromosome 14 may host a TSG that may lead to the development and/or progression of HNSCCs. Several genes such as CHES1, BMP4, SAV, and PNN have arisen as candidate tumor suppressors in the region.

Katoh H, Ojima H, Kokubu A, et al.
Genetically distinct and clinically relevant classification of hepatocellular carcinoma: putative therapeutic targets.
Gastroenterology. 2007; 133(5):1475-86 [PubMed] Related Publications
BACKGROUND & AIMS: The biological aggressiveness of hepatocellular carcinoma (HCC) and the lack of optimal therapeutic strategies have rendered the disease a major challenge. Highly heterogeneous genetic alteration profiles of HCC have made it difficult to identify effective tailor-made molecular therapeutic targets. Therefore, classification of HCC into genetically homogeneous subclasses would be of great worth to develop novel therapeutic strategies.
METHODS: We clarified genome-scale chromosomal copy number alteration profiles and mutational statuses of p53 and beta-catenin in 87 HCC tumors. We investigated the possibility that HCC might be classifiable into a number of homogeneous subclasses based solely on their genetic alteration profiles. We also explored putative molecular therapeutic targets specific for each HCC subgroup.
RESULTS: Unsupervised hierarchical cluster analysis based on chromosomal alteration profiles suggested that HCCs with heterogeneous genetic backgrounds are divisible into homogeneous subclasses that are highly associated with a range of clinicopathologic features of the tumors and moreover with clinical outcomes of the patients (P < .05). These genetically homogeneous subclasses could be characterized distinctively by pathognomonic chromosomal amplifications (eg, c-Myc-induced HCC, 6p/1q-amplified HCC, and 17q-amplified HCC). An in vitro experiment raised a possibility that Rapamycin would significantly inhibit the proliferative activities of HCCs with 17q amplification.
CONCLUSIONS: HCC is composed of several genetically homogeneous subclasses, each of which harbors characteristic genetic alterations that can be putative tailor-made molecular therapeutic targets for HCCs with specific genetic backgrounds. Our results offer an opportunity for developing novel individualized therapeutic modalities for distinctive genome types of HCC.

Whitney EM, Ghaleb AM, Chen X, Yang VW
Transcriptional profiling of the cell cycle checkpoint gene krüppel-like factor 4 reveals a global inhibitory function in macromolecular biosynthesis.
Gene Expr. 2006; 13(2):85-96 [PubMed] Free Access to Full Article Related Publications
Krüppel-like factor 4 (KLF4; also known as gut-enriched Krüppel-like factor or GKLF) is known to exhibit checkpoint function during the G1/S and G2/M transitions of the cell cycle. The mechanism by which KLF4 exerts these effects is not fully established. Here we investigated the expression profile of KLF4 in an inducible system over a time course of 24 h. Using oligonucleotide microarrays, we determined that the fold changes relative to control in expression levels of KLF4 exhibited a time-dependent increase from 3- to 20-fold between 4 and 24 h following KLF4 induction. During this period and among a group of 473 cell cycle regulatory genes examined, 96 were positively correlated and 86 were negatively correlated to KLF4's expression profile. Examples of upregulated cell cycle genes include those encoding tumor suppressors such as MCC and FHIT, and cell cycle inhibitors such as CHES1 and CHEK1. Examples of downregulated genes include those that promote the cell cycle including several cyclins and those required for DNA replication. Unexpectedly, several groups of genes involved in macromolecular synthesis, including protein biosynthesis, transcription, and cholesterol biosynthesis, were also significantly inhibited by KLF4. Thus, KLF4 exerts a global inhibitory effect on macromolecular biosynthesis that is beyond its established role as a cell cycle inhibitor.

Chang JT, Wang HM, Chang KW, et al.
Identification of differentially expressed genes in oral squamous cell carcinoma (OSCC): overexpression of NPM, CDK1 and NDRG1 and underexpression of CHES1.
Int J Cancer. 2005; 114(6):942-9 [PubMed] Related Publications
To identify cellular genes that could potentially serve as predictive molecular markers for human oral cancer, we employed differential display analysis to compare the gene expression profiles between oral squamous cell carcinoma (OSCC) and histopathologically normal epithelium tissues. Comparative real-time RT-PCR was used to confirm the gene expression in 52 OSCC patients, and a 2-fold difference was defined as over- or underexpression. A total of 7 genes were identified: NPM, CDK1, NDRG1, HMGCR, EF1A, NAC and CHES1. In the cancer tissues, NPM, CDK1 and NDRG1 were significantly overexpressed (an average of 7.6-, 17.2- and 12.9-fold, respectively), and CHES1 was underexpressed (15-fold). The frequencies of the differential expression were 40, 56, 67 and 46%, respectively in NPM, CDK1, NDRG1 and CHES1. In Western blot analysis, the protein expressions of NPM, CDK1 and NDRG1 were also increased in the cancer tissues, consistent with the mRNA expression results. To further evaluate clinicopathological associations in these genes, Pearson chi-square analysis was employed. Levels of CDK1 and NDRG1 were associated with poorly differentiated tumors (p = 0.043 and 0.023), suggesting that these genes participate in the mechanism of tumor transformation. Expressions of CDK1 and NDRG1, and CDK1 and CHES1 were mutually statistically correlated (p = 0.001 and 0.014), indicating that these genes share a very close regulatory relationship or interact synergistically in oncogenesis. In conclusion, we identified 7 genes that are differentially expressed in OSCC, and we provide the first evidence that NPM, CDK1 and NDRG1 are overexpressed and CHES1 is underexpressed in oral cancer. These results serve as a fundamental base for employing these genes in future clinical applications.

Katoh M, Katoh M
Human FOX gene family (Review).
Int J Oncol. 2004; 25(5):1495-500 [PubMed] Related Publications
Human Forkhead-box (FOX) gene family consists of at least 43 members, including FOXA1, FOXA2, FOXA3, FOXB1, FOXC1, FOXC2, FOXD1, FOXD2, FOXD3, FOXD4, FOXD5 (FOXD4L1), FOXD6 (FOXD4L3), FOXE1, FOXE2, FOXE3, FOXF1, FOXF2, FOXG1 (FOXG1B), FOXH1, FOXI1, FOXJ1, FOXJ2, FOXJ3, FOXK1, FOXK2, FOXL1, FOXL2, FOXM1, FOXN1, FOXN2 (HTLF), FOXN3 (CHES1), FOXN4, FOXN5 (FOXR1), FOXN6 (FOXR2), FOXO1 (FOXO1A), FOXO2 (FOXO6), FOXO3 (FOXO3A), FOXO4 (MLLT7), FOXP1, FOXP2, FOXP3, FOXP4, and FOXQ1. FOXE3-FOXD2 (1p33), FOXQ1-FOXF2-FOXC1 (6p25.3), and FOXF1-FOXC2-FOXL1 (16q24.1) loci are FOX gene clusters within the human genome. Members of FOX subfamilies A-G, I-L and Q were grouped into class 1 FOX proteins, while members of FOX subfamilies H and M-P were grouped into class 2 FOX proteins. C-terminal basic region within the FOX domain was the common feature of class 1 FOX proteins. FOXH1 and FOXO1 mRNAs are expressed in human embryonic stem (ES) cells. FOXC1, FOXC2, FOXE1, FOXE3, FOXL2, FOXN1, FOXP2 and FOXP3 genes are mutated in human congenital disorders. FOXA1 gene is amplified and over-expressed in esophageal and lung cancer. FOXM1 gene is up-regulated in pancreatic cancer and basal cell carcinoma due to the transcriptional regulation by Sonic Hedgehog (SHH) pathway. FOXO1 gene is fused to PAX3 or PAX7 genes in rhabdomyosarcoma. FOXO3 and FOXO4 genes are fused to MLL gene in hematological malignancies. Deregulation of FOX family genes leads to congenital disorders, diabetes mellitus, or carcinogenesis. Expression profiles, genetic alterations and epigenetic changes of FOX family genes as well as binding proteins and target genes of FOX family transcription factors should be comprehensively investigated to develop novel therapeutics and preventives for human diseases.

Katoh M, Katoh M
Identification and characterization of human FOXN6, mouse Foxn6, and rat Foxn6 genes in silico.
Int J Oncol. 2004; 25(1):219-23 [PubMed] Related Publications
Forkhead-box (FOX) transcription factors are implicated in carcinogenesis through gene amplification, retroviral integration, or chromosomal translocation. FOXN1, FOXN2 (HTLF), FOXN3 (CHES1), FOXN4 and FOXN5 (FOXR1) constitute the FOXN family. Here, we identified and characterized human FOXN6 (FOXR2) and rodent Foxn6 (Foxr2) orthologs by using bioinformatics. Human FOXN6 gene was identified within human genome sequence RP11-167P23 (AL159987.19), mouse Foxn6 gene within mouse genome sequence RP23-180D16 (AL672293.14), and rat Foxn6 gene within rat genome sequence CH230-264B14 (AC106980.5). FOXN6, RRAGB (RAGB), and KLF8 genes were clustered at human chromosome Xp11.21. Foxn6, Rragb, and Klf8 genes were also clustered at mouse chromosome XF3 as well as at rat chromosome Xq14. Human FOXN6 mRNA was expressed in breast cancer cell line and primary breast cancer. Mouse Foxn6 mRNA was expressed in E9.5 embryo. Human FOXN6 (286 aa) showed 57.7% total-amino-acid identity with human FOXN5, 53.8% total-amino-acid identity with mouse Foxn6 (277 aa), and 52.4% total-amino-acid identity with rat Foxn6 (277 aa). Codon 167-248 of human FOXN6 was the Forkhead domain. FN56 domain (codon 1-69 of FOXN6) was identified as a novel domain conserved among FOXN6 and FOXN5 orthologs. Mammalian FOXN6 orthologs were found consisting of FN56 and FOX domains. Phylogenetic analyses revealed that FOXN family proteins are classified into three subfamilies: i) FOXN6 and FOXN5 orthologs; ii) FOXN1 and FOXN4 orthologs; iii) FOXN2 and FOXN3 orthologs. This is the first report on human FOXN6, mouse Foxn6, and rat Foxn6 genes.

Hong Y, Müller UR, Lai F
Discriminating two classes of toxicants through expression analysis of HepG2 cells with DNA arrays.
Toxicol In Vitro. 2003; 17(1):85-92 [PubMed] Related Publications
Microarray technology provides a rapid and cost-effective method to associate specific cellular responses with unique gene expression patterns. If characteristic expression patterns of a small number of genes could be associated with drug toxicity, this association may be used for toxicity prediction, and thereby to reduce the need for traditional toxicity testing. To test this hypothesis, we have designed an array composed of 92 known human genes of toxicological interest (including seven housekeeping genes) and eight bacterial controls. HepG2 cells were treated with either ethanol or one of two quinone containing anticancer drugs, mitomycin C or doxorubicin. RNA was isolated from treated and untreated cells, differentially labeled with fluorescent dyes, and then hybridized to the array. Our results show that the expression patterns induced by ethanol and the anticancer drugs are different. Both of the anticancer drugs, but not ethanol had a differential effect on the regulation of several genes, including CYP4F2/3, CYP3A3, TNFRSF6 and CHES1, demonstrating that the two drugs might function through a similar mechanism, which differs from that of ethanol. These results suggest that microarray-based expression analysis may offer a rapid and efficient means for assessing drug toxicity.

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