Gene Summary

Gene:JUND; JunD proto-oncogene, AP-1 transcription factor subunit
Aliases: AP-1
Summary:The protein encoded by this intronless gene is a member of the JUN family, and a functional component of the AP1 transcription factor complex. This protein has been proposed to protect cells from p53-dependent senescence and apoptosis. Alternative translation initiation site usage results in the production of different isoforms (PMID:12105216). [provided by RefSeq, Nov 2013]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor jun-D
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
Show (13)
Pathways:What pathways are this gene/protein implicaed in?
Show (3)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 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.

  • Promoter Regions
  • Proto-Oncogene Proteins c-jun
  • JUN
  • Proto-Oncogene Proteins c-fos
  • Receptors, CCR4
  • DNA-Binding Proteins
  • Transcription Factors
  • Chromosome 19
  • siRNA
  • Immunohistochemistry
  • Gene Expression Profiling
  • Cell Nucleus
  • Molecular Sequence Data
  • Breast Cancer
  • Protein Binding
  • Apoptosis
  • Proto-Oncogene Proteins
  • Phenotype
  • Skin Cancer
  • Signal Transduction
  • Receptor Protein-Tyrosine Kinases
  • Tumor Suppressor Proteins
  • U937 Cells
  • JUND
  • Gene Expression
  • beta Catenin
  • Messenger RNA
  • Cancer Gene Expression Regulation
  • HeLa Cells
  • Multiple Endocrine Neoplasia Type 1
  • Lung Cancer
  • Base Sequence
  • Prostate Cancer
  • Pancreatic Cancer
  • Neoplasm Proteins
  • Cancer RNA
  • Mutation
  • Cell Proliferation
  • Oligonucleotide Array Sequence Analysis
  • Sequence Deletion
Tag cloud generated 11 March, 2017 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: JUND (cancer-related)

Tak E, Hwang S, Lee HC, et al.
Apoptosis of Hepatitis B Virus-expressing Liver Tumor Cells Induced by a High Concentration of Nucleos(t)ide Analogue.
Anticancer Res. 2016; 36(11):6059-6069 [PubMed] Related Publications
BACKGROUND/AIM: We investigated the expression of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and HBV X protein (HBx) in human hepatocellular carcinoma (HCC) and evaluated the effect of high-concentration nucleos(t)ide analogs (NUCs) on liver tumor cell lines.
MATERIALS AND METHODS: This study consisted of three parts: part I used human blood and non-tumor liver tissues; part II used human HCC and adjacent liver tissues; and part III used an HBV-expressing liver tumor cell line.
RESULTS: There were close correlations among blood and liver HBV DNA and liver cccDNA. HBV cccDNA and HBx were highly up-regulated in HCC compared to adjacent liver tissues despite NUC therapy. HBV cccDNA and HBx were highly up-regulated in the cccDNA-expressing HepG2.2.15 cell line. Their expression was down-regulated and apoptosis was induced by a very high concentration of NUCs in dose- and time-dependent manner.
CONCLUSION: Very high concentrations of NUCs may have a novel potential to kill replicating HBV-expressing liver tumor cells.

Yoo KD, Jun DW
Image of the Month: Viable Hepatocellular Carcinoma Foci in Radiological Complete Remission After Transarterial Embolization.
Am J Gastroenterol. 2016; 111(2):172 [PubMed] Related Publications

Andrs M, Korabecny J, Nepovimova E, et al.
Small Molecules Targeting Ataxia Telangiectasia and Rad3-Related (ATR) Kinase: An Emerging way to Enhance Existing Cancer Therapy.
Curr Cancer Drug Targets. 2016; 16(3):200-8 [PubMed] Related Publications
The main aim of current cancer research is to find a way to selectively affect the tumor cells, while leaving normal cells intact. Ataxia telangiectasia and Rad3-related kinase (ATR), a member of the phosphatidylinositol-3-related protein kinases (PIKK), represents a candidate target for achieving this goal. ATR kinase is one of the main kinases of the DNA damage response signaling pathway and responds to DNA damage caused by replication stress and various genotoxic agents (i.e. chemotherapy, ionizing radiation, ultraviolet light). ATR activation triggers cell cycle checkpoints, DNA repair and apoptosis, but also resistance of tumor cells to DNA damaging agents, through stress support under replication stress. Thus, the inhibition of ATR leads to increased effectiveness of cancer therapy and in addition enables highly selective targeting of cancer cells through synthetic lethal interactions. Despite this great potential, only a few potent and selective inhibitors of ATR kinase have been developed to date. However, those which have been developed provide great promise, and are under evaluation in many current preclinical and clinical trials. The purpose of this review is to summarize the potential of ATR inhibitors and the medicinal chemistry efforts which resulted in their identification.

Qifan W, Fen N, Ying X, et al.
iRGD-targeted delivery of a pro-apoptotic peptide activated by cathepsin B inhibits tumor growth and metastasis in mice.
Tumour Biol. 2016; 37(8):10643-52 [PubMed] Related Publications
The use of cytolytic peptides with potential therapeutic properties is a promising approach to cancer therapy due to their convenient automated synthesis and their capacity for modifications. However, the use of cytolytic peptides is limited due to their nonspecific cytolytic activity. In this study, we designed a tumor-targeting proapoptotic system based on an amphipathic D-amino acid-modified apoptotic peptide, KLA, a variant of (KLAKLAK)2, which is fused with a linear tumor-penetrating homing peptide iRGD through specific cathepsin B (CTSB) cleavage sequences that are overexpressed in many types of tumor tissues. Our data show that the procytotoxic peptide D(KLAKLAKKLAKLA)K-GG-iRGD (m(KLA)-iRGD) is internalized into cultured tumor cells through a neuropilin-1 (NRP1)-activated pathway by iRGD delivery. Once inside the cells, the peptide triggers rapid apoptosis through both the mitochondrial-induced apoptotic pathway and the death receptor pathway in NRP1+/αvβ3/CTSB+ tumor cells. Furthermore, m(KLA)-iRGD spread extensively within the tumor tissue when it was injected into 4T1 tumor-bearing mice. The m(KLA)-iRGD peptide inhibited tumor growth to a certain degree, resulting in a significant reduction in tumor volume (P < 0.05) and the total inhibition of metastasis at the end of the treatment. These results suggest that m(KLA)-iRGD has the potential for development as a new antitumor drug.

Jun DW, Hwang M, Kim YH, et al.
DDRI-9: a novel DNA damage response inhibitor that blocks mitotic progression.
Oncotarget. 2016; 7(14):17699-710 [PubMed] Free Access to Full Article Related Publications
The DNA damage response (DDR) is an emerging target for cancer therapy. By modulating the DDR, including DNA repair and cell cycle arrest, the efficacy of anticancer drugs can be enhanced and side effects reduced. We previously screened a chemical library and identified novel DDR inhibitors including DNA damage response inhibitor-9 (DDRI-9; 1H-Purine-2,6-dione,7-[(4-fluorophenyl)methyl]-3,7-dihydro-3-methyl-8-nitro). In this study, we characterized DDRI-9 activity and found that it inhibited phosphorylated histone variant H2AX foci formation upon DNA damage, delayed DNA repair, and enhanced the cytotoxicity of etoposide and ionizing radiation. It also reduced the foci formation of DNA repair-related proteins, including the protein kinase ataxia-telangiectasia mutated, DNA-dependent protein kinase, breast cancer type 1 susceptibility protein, and p53-binding protein 1, but excluding mediator of DNA damage checkpoint protein 1. Cell cycle analysis revealed that DDRI-9 blocked mitotic progression. Like other mitotic inhibitors, DDRI-9 treatment resulted in the accumulation of mitotic protein and induced cell death. Thus, DDRI-9 may affect both DDR signal amplification and mitotic progression. This study suggests that DDRI-9 is a good lead molecule for the development of anticancer drugs.

Liu X, Li H, Rajurkar M, et al.
Tead and AP1 Coordinate Transcription and Motility.
Cell Rep. 2016; 14(5):1169-80 [PubMed] Free Access to Full Article Related Publications
The Tead family transcription factors are the major intracellular mediators of the Hippo-Yap pathway. Despite the importance of Hippo signaling in tumorigenesis, Tead-dependent downstream oncogenic programs and target genes in cancer cells remain poorly understood. Here, we characterize Tead4-mediated transcriptional networks in a diverse range of cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 transcription factors to coordinate target gene transcription. We find that Tead-AP1 interaction is JNK independent but engages the SRC1-3 co-activators to promote downstream transcription. Furthermore, we show that Tead-AP1 cooperation regulates the activity of the Dock-Rac/CDC42 module and drives the expression of a unique core set of target genes, thereby directing cell migration and invasion. Together, our data unveil a critical regulatory mechanism underlying Tead- and AP1-controlled transcriptional and functional outputs in cancer cells.

Juilland M, Gonzalez M, Erdmann T, et al.
CARMA1- and MyD88-dependent activation of Jun/ATF-type AP-1 complexes is a hallmark of ABC diffuse large B-cell lymphomas.
Blood. 2016; 127(14):1780-9 [PubMed] Free Access to Full Article Related Publications
A hallmark of the diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) type, a molecular subtype characterized by adverse outcome, is constitutive activation of the transcription factor nuclear factor-κB (NF-κB), which controls expression of genes promoting cellular survival and proliferation. Much less, however, is known about the role of the transcription factor activator protein-1 (AP-1) in ABC DLBCL. Here, we show that AP-1, like NF-κB, was controlled by constitutive activation of the B-cell receptor signaling component caspase recruitment domain-containing membrane-associated guanylate kinase 1 (CARMA1) and/or the Toll-like receptor signaling component myeloid differentiation primary response gene 88 (MyD88) in ABC DLBCL cell lines. In contrast to germinal center (GC) B-cell (GCB) DLBCL, ABC DLBCL cell lines expressed high levels of the AP-1 family members c-Jun, JunB, and JunD, which formed heterodimeric complexes with the AP-1 family members activating transcription factor (ATF) 2, ATF3, and ATF7. Inhibition of these complexes by a dominant-negative approach led to impaired growth of a majority of ABC DLBCL cell lines. Individual silencing of c-Jun, ATF2, or ATF3 decreased cellular survival and revealed c-Jun/ATF2-dependent control of ATF3 expression. As a consequence, ATF3 expression was much higher in ABC vs GCB DLBCL cell lines. Samples derived from DLBCL patients showed a clear trend toward high and nuclear ATF3 expression in nodal DLBCL of the non-GC or ABC subtype. These findings identify the activation of AP-1 complexes of the Jun/ATF-type as an important element controlling the growth of ABC DLBCL.

Perakakis N, Flohr F, Kayser G, et al.
Multiple endocrine neoplasia type 1 associated with a new germline Men1 mutation in a family with atypical tumor phenotype.
Hormones (Athens). 2016 Jan-Mar; 15(1):113-7 [PubMed] Related Publications
BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant hereditary disorder associated with the development of endocrine tumors due to reduced expression of the tumor suppressor protein menin. Recent studies indicate a general role of menin in carcinogenesis, affecting the prevalence and clinical course of common non-endocrine tumors such as breast cancer, hepatocellular carcinoma and melanoma. Here we report a new germline missense mutation of Men1 in a German family with atypical tumor phenotype over three generations. Based on the type of mutation, we discuss possible changes in menin function leading to atypical tumorigenesis and present the clinical significance of such findings.
CASE PRESENTATION: A German family with a history of primary hyperparathyroidism presented to our Hospital for further evaluation. Members of the family demonstrated many different atypical tumors, such as renal cell carcinoma, papillary thyroid cancer and prostate cancer. DNA sequencing from peripheral blood revealed a novel mutation: Ser38Cys [TCC>TGC] in exon 2, codon 38 of Men1. This novel mutation is located in a region of menin which is responsible for interactions with the transcription factor JunD. This factor has recently been associated with prostate cancer. DNA sequencing of two of the atypical tumors (prostate cancer, papillary thyroid cancer) did not reveal a loss of heterozygosity, indicating an impact on menin expression and function in the heterozygous state, in line with results in +/-Men1 mutant mice developing prostate cancer.
CONCLUSION: The results and clinical course of disease in this case indicate the potential role of menin in the development of non-endocrine or atypical-endocrine tumors in MEN1 patients. Further investigations are needed to clarify both the general role of menin and the importance of specific mutations in carcinogenesis. Nevertheless, in families with uncommon manifestations of the syndrome early diagnostic adjustments should be considered.

Lee JH, Lee HL, Ahn YW, et al.
Prevalence of Gastric Subepithelial Tumors in Korea: A Single Center Experience.
Korean J Gastroenterol. 2015; 66(5):274-6 [PubMed] Related Publications
BACKGROUND/AIMS: The incidental finding of gastrointestinal subepithelial tumors (SETs) is increasing with national cancer screening endoscopy. In a Swedish population, screening endoscopy found a prevalence of SETs of 0.36%. However, the prevalence of gastric SETs in Korean patients has not been described. Therefore, this study evaluated the prevalence of SETs of the stomach in a Korean patient population.
METHODS: We reviewed endoscopic reports of 11,712 subjects who underwent screening esophagogastroduodenoscopy (EGD) at Hanyang University Hospital between July 2012 and June 2013.
RESULTS: Among 11,712 patients, 194 (1.7%) had SET of the stomach. Of these, 71 (prevalence, 0.6%) were male and 123 (prevalence, 1.1%) were female. When grouped by age, the prevalence of SET was as follows: 1.0% for patients in their twenties, 6.2% for those in their thirties, 19.1% for those in their forties, 33.0% for those in their fifties, 30.4% for those in their sixties, and 10.3% for those over 70 years of age.
CONCLUSIONS: The overall prevalence of gastric SET among healthy examinees was 1.7%. The prevalence of gastric SET increased with age and was higher in female.

Sheng L, Wang Y, Jun D, Peihong W
[Comparison of the effectiveness of percutaneous microwave ablation versus hepatectomy for hepatocellular carcinoma].
Zhonghua Zhong Liu Za Zhi. 2015; 37(4):301-7 [PubMed] Related Publications
OBJECTIVE: To compare the effectiveness of percutaneous microwave ablation ( MWA) versus hepatectomy for multifocal hepatocellular carcinoma.
METHODS: From August 2002 to March 2012, one hundred and twenty-two patients with multifocal hepatocellular carcinoma (diameters 1 to 7 cm, 2 to 4 lesions) were treated by either complete MWA or radical hepatectomy, and their clinical data were collected and analyzed.The patients were divided into MWA group (n = 50) and resection group (n = 72), and the resection group was matched by MWA group based on clinical parameters. The survival and complications in the two groups were compared.
RESULTS: The overall 1-, 3- and 5-year survival rates were 100.0%, 73.0% and 62.0%, respectively, in the MWA group, and 80.0%, 56.0%, and 41.0%, respectively, in the resection group (P < 0.05). The corresponding recurrence-free survival rates were 88.0%, 63.0%, and 52.0% in the MWA group, and 68.0%, 45.0%, and 36.0%, respectively, in the resection group (P< 0.05). The multivariate Cox regression analysis indicated that albumin level, performance status, treatment modality, and tumor size were independent prognostic factors.
CONCLUSION: Compared with hepatectomy, percutaneous microwave ablation is a minimally invasive and reproducible procedure, and can improve the survival in patients with multifocal hepatocellular carcinoma.

Thevenon J, Bourredjem A, Faivre L, et al.
Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study.
Eur J Endocrinol. 2015; 173(6):819-26 [PubMed] Related Publications
BACKGROUND: MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1.
METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software.
RESULTS: Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs.
CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

Yu D, Jun D, Qing Y, Jianxun Z
Development of a noninvasive electrical impedance probe for minimally invasive tumor localization.
Physiol Meas. 2015; 36(9):1785-99 [PubMed] Related Publications
Compared with traditional open surgery, minimally invasive surgery (MIS) improves the accuracy and dexterity of a surgeon and minimizes trauma to the patient. However, the lack of significant haptic feedback in MIS can make tumor localization difficult. A noninvasive electrical impedance probe (NEIP), consisting mainly of two spherical electrodes and a constant force generator, has been developed to gently touch or slide over tissue surface and at the same time record impedance values without prior registration of the surface. We prove that there is a linear relationship between the surgical margin width and the recorded conductance. Ex vivo experiments in ten human kidney specimens were performed to demonstrate the feasibility of NEIP. The experimental results verify the linear relationship and indicate that NEIP can provide accurate tumor location while sliding over the tissue surface.

Khan FH, Pandian V, Ramraj S, et al.
Reorganization of metastamiRs in the evolution of metastatic aggressive neuroblastoma cells.
BMC Genomics. 2015; 16:501 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MetastamiRs have momentous clinical relevance and have been correlated with disease progression in many tumors. In this study, we identified neuroblastoma metastamiRs exploiting unique mouse models of favorable and high-risk metastatic human neuroblastoma. Further, we related their deregulation to the modulation of target proteins and established their association with clinical outcomes.
RESULTS: Whole genome miRNA microarray analysis identified 74 metastamiRs across the manifold of metastatic tumors. RT-qPCR on select miRNAs validated profile expression. Results from bio-informatics across the ingenuity pathway, miRCancer, and literature data-mining endorsed the expression of these miRNAs in multiple tumor systems and showed their role in metastasis, identifying them as metastamiRs. Immunoblotting and TMA-IHC analyses revealed alterations in the expression/phosphorylation of metastamiRs' targets, including ADAMTS-1, AKT1/2/3, ASK1, AURKβ, Birc1, Birc2, Bric5, β-CATENIN, CASP8, CD54, CDK4, CREB, CTGF, CXCR4, CYCLIN-D1, EGFR, ELK1, ESR1, CFOS, FOSB, FRA, GRB10, GSK3β, IL1α, JUND, kRAS, KRTAP1, MCP1, MEGF10, MMP2, MMP3, MMP9, MMP10, MTA2, MYB, cMYC, NF2, NOS3, P21, pP38, PTPN3, CLEAVED PARP, PKC, SDF-1β, SEMA3D, SELE, STAT3, TLR3, TNFα, TNFR1, and VEGF in aggressive cells ex vivo and in a manifold of metastatic tumors in vivo. miRNA mimic (hsa-miR-125b, hsa-miR-27b, hsa-miR-93, hsa-miR-20a) and inhibitor (hsa-miR-1224-3p, hsa-miR-1260) approach for select miRNAs revealed the direct influence of the altered metastamiRs in the regulation of identified protein targets. Clinical outcome association analysis with the validated metastamiRs' targets corresponded strongly with poor overall and relapse-free survival.
CONCLUSIONS: For the first time, these results identified a comprehensive list of neuroblastoma metastamiRs, related their deregulation to altered expression of protein targets, and established their association with poor clinical outcomes. The identified set of distinctive neuroblastoma metastamiRs could serve as potential candidates for diagnostic markers for the switch from favorable to high-risk metastatic disease.

Raval GU, Bidoia C, Forlani G, et al.
Localization, quantification and interaction with host factors of endogenous HTLV-1 HBZ protein in infected cells and ATL.
Retrovirology. 2015; 12:59 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human T cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of a severe form of neoplasia designated Adult T cell Leukaemia (ATL). It is widely accepted that the viral transactivator Tax-1 is the major viral product involved in the onset, but not in the maintenance, of neoplastic phenotype, as only 30-40% of ATL cells express Tax-1. It has been recently demonstrated that HBZ (HTLV-1 bZIP factor), a protein encoded by the minus strand of HTLV-1 genome, constantly expressed in infected cells and in ATL tumor cells, is also involved in the pathogenesis of leukaemia. The full role played by HBZ in oncogenesis is not clarified in detail also because of the limited availability of tools to assess quantitative expression, subcellular location and interaction of HBZ with host factors in ATL.
RESULTS: By the use of the first reported monoclonal antibody against HBZ, 4D4-F3, generated in our laboratory it has been possible to carefully assess for the first time the above parameters in HTLV-1 chronically infected cells and, most importantly, in fresh leukemic cells from patients. Endogenous HBZ is expressed in speckle-like structures localized in the nucleus. The calculated number of endogenous HBZ molecules varies between 17.461 and 39.615 molecules per cell, 20- to 50-fold less than the amount expressed in HBZ transfected cells used by most investigators to assess the expression, function and subcellular localization of the viral protein. HBZ interacts in vivo with p300 and JunD and co-localizes only partially, and depending on the amount of expressed HBZ, not only with p300 and JunD but also with CBP and CREB2.
CONCLUSIONS: The possibility to study endogenous HBZ in detail may significantly contribute to a better delineation of the role of HBZ during HTLV-1 infection and cellular transformation.

Oranger A, Brunetti G, Carbone C, et al.
Human myeloma cell lines induce osteoblast downregulation of CD99 which is involved in osteoblast formation and activity.
J Immunol Res. 2015; 2015:156787 [PubMed] Free Access to Full Article Related Publications
CD99 is a transmembrane glycoprotein expressed in physiological conditions by cells of different tissues, including osteoblasts (OBs). High or low CD99 levels have been detected in various pathological conditions, and the supernatant of some carcinoma cell lines can modulate CD99 expression in OB-like cells. In the present work we demonstrate for the first time that two different human myeloma cell lines (H929 and U266) and, in a less degree, their conditioned media significantly downregulate CD99 expression in normal human OBs during the differentiation process. In the same experimental conditions the OBs display a less differentiated phenotype as demonstrated by the decreased expression of RUNX2 and Collagen I. On the contrary, when CD99 was activated by using a specific agonist antibody, the OBs become more active as demonstrated by the upregulation of Alkaline Phosphatase, Collagen I, RUNX2, and JUND expression. Furthermore, we demonstrate that the activation of CD99 is able to induce the phosphorylation of ERK 1/2 and AKT intracellular signal transduction molecules in the OBs.

Park SW, Lee HL, Doo EY, et al.
Visceral Obesity Predicts Fewer Lymph Node Metastases and Better Overall Survival in Colon Cancer.
J Gastrointest Surg. 2015; 19(8):1513-21 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The relationship between visceral obesity and colon cancer outcome has not been well studied. The goal of this study was to determine the impact of visceral obesity on lymph node (LN) metastasis and overall survival (OS) in colon cancer.
MATERIALS AND METHODS: Metastatic LN ratio (MLR) was defined as the number of involved nodes by tumor divided by the total number of resected LNs. Visceral (VFA) and subcutaneous fat areas (SFA) were determined by measuring abdominal fat volume distribution via CT scan, and visceral obesity was defined as a VFA to total fat area ratio (V/T) > 0.29.
RESULTS: In a multivariate analysis among 186 patients, there were inverse associations between V/T and MLR (OR = 0.413, 95% CI = 0.216-0.789, P = 0.007). Furthermore, patients with visceral obesity tended to have significantly better OS than patients with non-visceral obesity.
CONCLUSIONS: Higher V/T ratios which indicate referring to visceral obesity was significantly associated with decreased MLR and better OS for CRC.

Akter S, Choi TG, Nguyen MN, et al.
Prognostic value of a 92-probe signature in breast cancer.
Oncotarget. 2015; 6(17):15662-80 [PubMed] Free Access to Full Article Related Publications
Clinical applications of gene expression signatures in breast cancer prognosis still remain limited due to poor predictive strength of single training datasets and appropriate invariable platforms. We proposed a gene expression signature by reducing baseline differences and analyzing common probes among three recent Affymetrix U133 plus 2 microarray data sets. Using a newly developed supervised method, a 92-probe signature found in this study was associated with overall survival. It was robustly validated in four independent data sets and then repeated on three subgroups by incorporating 17 breast cancer microarray datasets. The signature was an independent predictor of patients' survival in univariate analysis [(HR) 1.927, 95% CI (1.237-3.002); p < 0.01] as well as multivariate analysis after adjustment of clinical variables [(HR) 7.125, 95% CI (2.462-20.618); p < 0.001]. Consistent predictive performance was found in different multivariate models in increased patient population (p = 0.002). The survival signature predicted a late metastatic feature through 5-year disease free survival (p = 0.006). We identified subtypes within the lymph node positive (p < 0.001) and ER positive (p = 0.01) patients that best reflected the invasive breast cancer biology. In conclusion using the Common Probe Approach, we present a novel prognostic signature as a predictor in breast cancer late recurrences.

Kim JO, Jun DW, Tae HJ, et al.
Low-dose steroid-induced tumor lysis syndrome in a hepatocellular carcinoma patient.
Clin Mol Hepatol. 2015; 21(1):85-8 [PubMed] Free Access to Full Article Related Publications
Tumor lysis syndrome is rare in hepatocellular carcinoma (HCC), but it has been reported more frequently recently in response to treatments such as transcatheter arterial chemoembolization (TACE), radiofrequency thermal ablation (RFTA), and sorafenib. Tumor lysis syndrome induced by low-dose steroid appears to be very unusual in HCC. We report a patient with hepatitis-C-related liver cirrhosis and HCC in whom tumor lysis syndrome occurred due to low-dose steroid (10 mg of prednisolone). The patient was a 90-year-old male who presented at the emergency room of our hospital with general weakness and poor oral intake. He had started to take prednisolone to treat adrenal insufficiency 2 days previously. Laboratory results revealed hyperuricemia, hyperphosphatemia, and increased creatinine. These abnormalities fulfilled the criteria in the Cairo-Bishop definition of tumor lysis syndrome. Although the patient received adequate hydration, severe metabolic acidosis and acute kidney injury progressed unabated. He finally developed multiple organ failure, and died 3 days after admission. This was a case of tumor lysis syndrome caused by administration of low-dose steroid in a patient with HCC.

Papoudou-Bai A, Goussia A, Batistatou A, et al.
The expression levels of JunB, JunD and p-c-Jun are positively correlated with tumor cell proliferation in diffuse large B-cell lymphomas.
Leuk Lymphoma. 2016; 57(1):143-50 [PubMed] Related Publications
We analyzed the expression of Jun family in relation to CD30 expression, cell proliferation and B-cell differentiation immunophenotypes [Germinal Center and non-Germinal Center] in diffuse large B-cell lymphomas (DLBCL). Expression and high expression of phosphorylated-c-Jun (p-c-Jun), JunB, JunD and CD30 (cut-off scores 20% and 50%, respectively) was found in 18/103, 49/103, 72/101 and 26/102 cases, respectively, and in 6/103, 27/103, 60/101 and 21/102 cases, respectively. The following significant positive correlations were observed: (a) JunB with cyclin A (p = 0.046), cyclin B1 (p = 0.033), cyclin E (p = 0.003), MUM-1 (p = 0.002) and CD30 (p < 0.001), (b) JunD with Ki67 (p = 0.002) and cyclin E (p = 0.014), (c) p-c-Jun with CD30 (p = 0.015), and (d) high p-c-Jun with cyclin A (p = 0.034). The positive correlation between expression of JunB, JunD and p-c-Jun and tumor cell proliferation in DLBCL, suggests that increased JunB, JunD and p-c-Jun expression may be involved in the pathogenesis of DLBCL by increasing tumor cell proliferation.

Gao C, Yu Z, Liu S, et al.
Overexpression of CUGBP1 is associated with the progression of non-small cell lung cancer.
Tumour Biol. 2015; 36(6):4583-9 [PubMed] Related Publications
The multifunctional RNA-binding protein CUGBP1 regulates multiple aspects of nuclear and cytoplasmic messenger RNA (mRNA) processing, including splicing, stabilization, and translation of mRNAs. Previous studies have shown that CUGBP1 is overexpressed in non-small-cell lung cancer (NSCLC) tissues, but the pathological functions of CUGBP1 in tumorigenesis and development are unknown. Here, we provide the first evidence demonstrating the clinicopathological significance of CUGBP1 in NSCLC. Using immunohistochemistry, the levels of CUGBP1 expression in NSCLC tissues and adjacent non-cancerous tissues were examined and determined to be associated with differentiation. Short hairpin RNA-induced downregulation of CUGBP1 promoted apoptosis and decreased proliferation in the A549 NSCLC cell line. Moreover, Western blot analysis indicated that the depletion of CUGBP1 increased the protein levels of cyclin D1, BAD, BAX, Jun D, and E-cadherin, while the cyclin B1 level decreased. Knockdown of CUGBP1 decreased β-catenin and vimentin levels and increased E-cadherin expression, suggesting that CUGBP1 may contribute significantly to epithelial to mesenchymal transition (EMT) progression. These results demonstrate the importance of CUGBP1 in the biological and pathological functions of NSCLC and indicate its potential as a therapeutic target for NSCLC.

Xu L, Wang T, Meng WY, et al.
Salinomycin inhibits hepatocellular carcinoma cell invasion and migration through JNK/JunD pathway-mediated MMP9 expression.
Oncol Rep. 2015; 33(3):1057-63 [PubMed] Free Access to Full Article Related Publications
The antibiotic salinomycin (Salin) was recently identified as an antitumor drug for the treatment of several types of solid tumors. However, the effects of Salin on the migratory and invasive properties of hepatocellular carcinoma (HCC) cells are unclear. The present study aimed to determine the antitumor efficacy and mechanism of Salin in HCC cells. Human HCC cells (HCCLM3) treated with Salin showed a concentration-dependent reduction in cell migration and invasion, and this was associated with reduced MMP9 expression. The MMP9 promoter and enhancer in a luciferase reporter assay revealed that Salin can regulate MMP9 expression through an activator protein (AP-1) site within the MMP9 enhancer. JunD, one of the AP-1 components, was significantly decreased by Salin in a concentration- and time-dependent manner. Salin was able to induce c-Jun NH2-kinase (JNK) phosphorylation and to block both JunD and MMP9 expression. Our results showed that JNK phosphorylation and JunD may be involved in the Salin-regulated MMP9 signaling pathway in HCCLM3 cells and may mediate HCC cell biological characteristics. Our studies provide new insight into the antitumor effects of Salin.

Park SW, Lee HL, Ju YW, et al.
Inverse association between visceral obesity and lymph node metastasis in gastric cancer.
J Gastrointest Surg. 2015; 19(2):242-50 [PubMed] Related Publications
BACKGROUND: The relationship between fat distribution and lymph node metastasis has not been well studied. The goal of this study was to determine the impact of visceral obesity on lymph node metastasis in gastric cancer.
MATERIALS AND METHODS: Metastatic lymph node ratio (MLR) was defined as the number of involved nodes by tumor divided by the total number of resected lymph nodes. Visceral (VFA) and subcutaneous fat areas (SFA) were determined by measuring abdominal fat volume distribution via CT scan, and visceral obesity was defined as a VFA to total fat area ratio (V/T) >0.29.
RESULTS: With lymph node metastasis as a dependent variable, the following factors were significant in multivariate analysis among 495 patients: pathologic T stage (P < 0.001), lympho-vascular invasion (P < 0.001), and V/T (hazard ratio (HR) = 0.455, 95 % confidence interval (CI) = 0.263-0.786, P = 0.005). Similarly, when MLR was the dependent variable in multivariate analysis, MLR was significantly associated with lympho-vascular invasion (HR = 2.222, 95 % CI = 1.149-4.296, P = 0.018), and V/T (HR = 0.247, 95 % CI = 0.133-0.458, P < 0.001).
CONCLUSIONS: Visceral obesity defined by higher visceral to total fat area ratio was significantly associated with decreased MLR.

Selvaraj N, Budka JA, Ferris MW, et al.
Extracellular signal-regulated kinase signaling regulates the opposing roles of JUN family transcription factors at ETS/AP-1 sites and in cell migration.
Mol Cell Biol. 2015; 35(1):88-100 [PubMed] Free Access to Full Article Related Publications
JUN transcription factors bind DNA as part of the AP-1 complex, regulate many cellular processes, and play a key role in oncogenesis. The three JUN proteins (c-JUN, JUNB, and JUND) can have both redundant and unique functions depending on the biological phenotype and cell type assayed. Mechanisms that allow this dynamic switching between overlapping and distinct functions are unclear. Here we demonstrate that JUND has a role in prostate cell migration that is the opposite of c-JUN's and JUNB's. RNA sequencing reveals that opposing regulation by c-JUN and JUND defines a subset of AP-1 target genes with cell migration roles. cis-regulatory elements for only this subset of targets were enriched for ETS factor binding, indicating a specificity mechanism. Interestingly, the function of c-JUN and JUND in prostate cell migration switched when we compared cells with an inactive versus an active RAS/extracellular signal-regulated kinase (ERK) signaling pathway. We show that this switch is due to phosphorylation and activation of JUND by ERK. Thus, the ETS/AP-1 sequence defines a unique gene expression program regulated by the relative levels of JUN proteins and RAS/ERK signaling. This work provides a rationale for how transcription factors can have distinct roles depending on the signaling status and the biological function in question.

Hajingabo LJ, Daakour S, Martin M, et al.
Predicting interactome network perturbations in human cancer: application to gene fusions in acute lymphoblastic leukemia.
Mol Biol Cell. 2014; 25(24):3973-85 [PubMed] Free Access to Full Article Related Publications
Genomic variations such as point mutations and gene fusions are directly or indirectly associated with human diseases. They are recognized as diagnostic, prognostic markers and therapeutic targets. However, predicting the functional effect of these genetic alterations beyond affected genes and their products is challenging because diseased phenotypes are likely dependent of complex molecular interaction networks. Using as models three different chromosomal translocations-ETV6-RUNX1 (TEL-AML1), BCR-ABL1, and TCF3-PBX1 (E2A-PBX1)-frequently found in precursor-B-cell acute lymphoblastic leukemia (preB-ALL), we develop an approach to extract perturbed molecular interactions from gene expression changes. We show that the MYC and JunD transcriptional circuits are specifically deregulated after ETV6-RUNX1 and TCF3-PBX1 gene fusions, respectively. We also identified the bulk mRNA NXF1-dependent machinery as a direct target for the TCF3-PBX1 fusion protein. Through a novel approach combining gene expression and interactome data analysis, we provide new insight into TCF3-PBX1 and ETV6-RUNX1 acute lymphoblastic leukemia.

Bartsch DK, Slater EP, Albers M, et al.
Higher risk of aggressive pancreatic neuroendocrine tumors in MEN1 patients with MEN1 mutations affecting the CHES1 interacting MENIN domain.
J Clin Endocrinol Metab. 2014; 99(11):E2387-91 [PubMed] Related Publications
CONTEXT: Sixty to 80% of multiple endocrine neoplasia type 1 (MEN1) patients develop pancreatic neuroendocrine neoplasias (pNENs), which reveal an aggressive behavior in 10%-20% of patients. Causative MEN1 mutations in the interacting domains of the encoded Menin protein directly alter its regulation abilities and may influence the phenotype.
OBJECTIVE: The objective of the study was the evaluation of an association between MEN1 mutations in different interacting domains of Menin and the phenotype of pNENs.
DESIGN: This was a retrospective analysis of a prospectively collected cohort of 71 genetically confirmed MEN1 patients at a tertiary referral center.
MAIN OUTCOME MEASURES: Analysis of patients' characteristics and clinical phenotype of pNENs regarding the mutation type and its location in Menin interacting domains was measured.
RESULTS: Sixty-seven patients (93%) developed pNENs after a median follow-up of 134 months. Patients with mutations leading to loss of interaction (LOI) with the checkpoint kinase 1 (CHES1) interacting domain codons (428-610) compared with patients with mutations resulting in LOI with other domains (eg, JunD, Smad3) had significantly higher rates of functioning pNENs (70% vs 34%), malignant pNENs (59% vs 16%), and aggressive pNENs (37% vs 9%), respectively. Patients with CHES1-LOI also had an increased pNEN-related mortality (20% vs 4.5%). Neither gender, age, nor the ABO blood types were associated with the phenotype of pNENs.
CONCLUSIONS: MEN1 patients with MEN1 mutations leading to CHES1-LOI have a higher risk of malignant pNENs with an aggressive course of disease and disease-related death.

Andrs M, Korabecny J, Nepovimova E, et al.
The development of ataxia telangiectasia mutated kinase inhibitors.
Mini Rev Med Chem. 2014; 14(10):805-11 [PubMed] Related Publications
Radiation and genotoxic drugs are two of the cornerstones of current cancer treatment strategy. However, this type of therapy often suffers from radio- or chemo-resistance caused by DNA repair mechanisms. With the aim of increasing the efficacy of these treatments, there has been great interest in studying DNA damage responses (DDR). Among the plethora of signal and effector proteins involved in DDR, three related kinases ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related) and DNA-PK (DNA-dependent protein kinase) play the main roles in initiation and regulation of signaling pathways in response to DNA double and single strand breaks (DSB and SSB). ATM inhibitors, as well as those of ATR and DNA-PK, provide an opportunity to sensitize cancer cells to therapy. Moreover, they can lead to selective killing of cancer cells, exploiting a concept known as synthetic lethality. However, only a very few selective inhibitors have been identified to this date. This mini-review is focused both on the development of selective inhibitors of ATM and other inhibitors which have ATM as one of their targets.

Tae HJ, Lee HL, Lee KN, et al.
Deep biopsy via endoscopic submucosal dissection in upper gastrointestinal subepithelial tumors: a prospective study.
Endoscopy. 2014; 46(10):845-50 [PubMed] Related Publications
BACKGROUND AND STUDY AIMS: Preoperative pathological diagnosis may improve clinical management decisions in patients with upper gastrointestinal subepithelial tumors (SETs). The aims of this study were to evaluate the diagnostic yield of deep biopsy via an endoscopic submucosal dissection (ESD) technique, the complications associated with the procedure, and the impact on management of patients with upper gastrointestinal SETs.
PATIENTS AND METHODS: A total of 68 patients with SETs in the stomach or esophagus were voluntarily assigned to two groups. One group underwent endoscopic ultrasound (EUS) and endoscopic deep biopsy using the ESD technique (40 patients), and the other group (28 patients) underwent surgical resection after EUS without obtaining preoperative pathological diagnosis, in accordance with accepted clinical management algorithms.
RESULTS: The diagnostic yield of deep biopsy was 90 % (36/40). The results of deep biopsy changed the treatment plans in 14/40 patients (35 %). One patient with lymphoepithelial carcinoma was scheduled for surgical resection, and 13 patients with benign SETs of diameter ≥  2 cm avoided surgery. Of the 28 patients who underwent surgical resection without preoperative pathological diagnosis, 12 (42.9 %) were confirmed to have benign lesions. The mean procedure time for deep biopsy was 13.7 minutes. There were no procedure-related complications in the deep biopsy group. 
CONCLUSIONS: Deep biopsy by the ESD technique is a safe, high-yield, diagnostic method in patients with upper gastrointestinal SETs. Pathologic confirmation could improve clinical decision making in the management of patients with upper gastrointestinal SETs.

Drayton RM, Peter S, Myers K, et al.
MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer.
Oncotarget. 2014; 5(15):6375-86 [PubMed] Free Access to Full Article Related Publications
Urothelial cell carcinoma of the bladder (UCC) is a common disease often characterized by FGFR3 dysregulation. Whilst upregulation of this oncogene occurs most frequently in low-grade non-invasive tumors, recent data reveal increased FGFR3 expression characterizes a common sub-type of invasive UCC sharing molecular similarities with breast cancer. These similarities include upregulation of the FOXA1 transcription factor and reduced expression of microRNAs-99a/100. We have previously identified direct regulation of FGFR3 by these two microRNAs and now search for further targets. Using a microarray meta-database we find potential FOXA1 regulation by microRNAs-99a/100. We confirm direct targeting of the FOXA1 3'UTR by microRNAs-99a/100 and also potential indirect regulation through microRNA-485-5p/SOX5/JUN-D/FOXL1 and microRNA-486/FOXO1a. In 292 benign and malignant urothelial samples, we find an inverse correlation between the expression of FOXA1 and microRNAs-99a/100 (r=-0.33 to -0.43, p<0.05). As for FGFR3 in UCC, tumors with high FOXA1 expression have lower rates of progression than those with low expression (Log rank p=0.009). Using global gene expression and CpG methylation profiling we find genotypic consequences of FOXA1 upregulation in UCC. Genetic changes are associated with regional hypomethylation, occur near FOXA1 binding sites, and mirror gene expression changes previously reported in FGFR3 mutant-UCC. These include gene silencing through aberrant hypermethylation (e.g. IGFBP3) and affect genes characterizing breast cancer sub-types (e.g. ERBB2). In conclusion, we have identified microRNAs-99a/100 mediate a direct relationship between FGFR3 and FOXA1 and potentially facilitate cross talk between these pathways in UCC.

Muñoz-Gámez JA, López Viota J, Barrientos A, et al.
Synergistic cytotoxicity of the poly (ADP-ribose) polymerase inhibitor ABT-888 and temozolomide in dual-drug targeted magnetic nanoparticles.
Liver Int. 2015; 35(4):1430-41 [PubMed] Related Publications
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is associated with a poor prognosis because of a lack of effective treatment options. The objective of this study was to examine a new strategy for HCC treatment, namely the use of poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor (ABT-888) together with Temozolomide (TMZ) incorporated onto magnetic nanoparticles.
METHODS: Magnetic Fe3 O4 /Fe cores were encapsulated within a silica shell to facilitate the simultaneous incorporation of ABT-888 and TMZ. In vitro tests were performed with HepG2, Hep3B and PLC-PRF-5 liver tumoural cell lines and with WRL-68 liver non-tumoural cells.
RESULTS: The magnetic nanocarriers were loaded simultaneously with ABT-888 and TMZ. High stability and extended release were achieved in culture medium. Confocal microscopy images showed that drug-loaded particles were uptaken and accumulated into the cytoplasm of liver tumoural cells, inducing the following effects: G2/M cell cycle arrest (P < 0.05), accumulation of DNA damage (P < 0.05), mitochondrial depolarization (P < 0.01), reduction in BCL-xL, FOS, JUND gene expression (P < 0.05), PARP-1 fragmentation, Caspase-3 activation and apoptotic cell death (P < 0.05). Interestingly, drugs loaded onto nanoparticles exhibited better efficiency than free drugs (cell death triggered by drug delivery nanosystem: 53.5% vs. 34.5% by free drugs, P = 0.01).
CONCLUSIONS: These magnetic nanocompounds are able to incorporate both drugs simultaneously, enter the tumour cells and release them. ABT-888/TMZ/NPs decrease the transcription of key genes involved in tumour survival and induce apoptotic cell death in a more effective manner than is achieved by free drugs.

Michor F, Weaver VM
Understanding tissue context influences on intratumour heterogeneity.
Nat Cell Biol. 2014; 16(4):301-2 [PubMed] Free Access to Full Article Related Publications
Although human cancers exhibit intratumour heterogeneity, the influence of the tumour environment on this property is unclear. Single basal-like mammary epithelial cells are now shown to engage a dynamic TGFBR3-JUND signalling circuit in an extracellular-matrix-dependent manner. Cell transition between the distinct gene expression states underlying this circuit alters their properties and may modulate their propensity to malignancy.

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