MYCBP

Gene Summary

Gene:MYCBP; MYC binding protein
Aliases: AMY-1
Location:1p33-p32.2
Summary:The protein encoded by this gene binds to the N-terminus of the oncogenic protein C-MYC, enhancing the ability of C-MYC to activate E box-dependent transcription. The encoded protein is normally found in the cytoplasm, but it translocates to the nucleus during S phase of the cell cycle and associates with C-MYC. This protein may be involved in spermatogenesis. This gene can be silenced by microRNA-22. Two transcript variants, one protein-coding and the other probably not protein-coding, have been found for this gene. [provided by RefSeq, Nov 2011]
Databases:VEGA, OMIM, HGNC, GeneCard, Gene
Protein:C-Myc-binding protein
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
Show (9)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

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

  • Messenger RNA
  • FISH
  • Disease Progression
  • Up-Regulation
  • Cerebellar Neoplasms
  • Tumor Markers
  • Transforming Growth Factor beta
  • Neoplastic Cell Transformation
  • Principal Component Analysis
  • Chromosome 1
  • DNA-Binding Proteins
  • Neoplasms, Experimental
  • Prostate Cancer
  • Western Blotting
  • Cluster Analysis
  • Immunohistochemistry
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Cell Proliferation
  • Telomerase
  • Oligonucleotide Array Sequence Analysis
  • Signal Transduction
  • Cancer RNA
  • Breast Cancer
  • p53 Protein
  • Gene Expression Profiling
  • Cell Differentiation
  • MicroRNAs
  • Single Nucleotide Polymorphism
  • Childhood Cancer
  • Retinoic Acid
  • Apoptosis
  • RTPCR
  • Cancer Gene Expression Regulation
  • myc Genes
  • Young Adult
  • Genomics
  • Gene Expression
  • Transcription
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: MYCBP (cancer-related)

Jeon HM, Kim do H, Jung WH, Koo JS
Expression of cell metabolism-related genes in different molecular subtypes of triple-negative breast cancer.
Tumori. 2013 Jul-Aug; 99(4):555-64 [PubMed] Related Publications
AIMS AND BACKGROUND: We evaluated the difference in and significance of cancer cell metabolism by molecular subtyping of triple-negative breast carcinoma.
METHODS: Tissue microarrays from 122 surgical specimens of triple-negative breast carcinoma patients and immunohistochemical staining for CK5/6, epidermal growth factor receptor, claudin 3, claudin 4, claudin 7, E-cadherin, androgen receptor, and gamma-glutamyltransferase 1 were used to classify triple-negative breast carcinoma as follows: basal-like type, molecular apocrine type, claudin low type, mixed type and null type. In addition, immunohistochemical staining for metabolism-related proteins such as c-myc, insulin-like growth factor (g)-1, hypoxia-inducible factor 1-1α, glucose transporter 1, carbonic anhydrase IX antibody, macrophage migration inhibitory factor, and pyruvate dehydrogenase kinase 1 was used to compare the differences according to molecular subtype and clinicopathological factors.
RESULTS: The basal-like type showed the highest proportion of high glucose transporter 1 expression (P = 0.049) and carbonic anhydrase IX antibody expression (P = 0.008). Hypoxia-inducible factor 1-1α expression was associated with lymph node metastasis (P = 0.001) and central fibrotic zone (P = 0.012), and high glucose transporter 1 expression was related to high histologic grade (P = 0.007), cytokeratin 5/6 positivity (P = 0.002), and central fibrotic zone (P = 0.017). Finally, carbonic anhydrase IX antibody was associated with cytokeratin 5/6 positivity (P = 0.001) and central fibrotic zone (P = 0.048).
CONCLUSIONS: Our study revealed the different characteristics of cancer cell metabolism according to the molecular subtypes of triple-negative breast carcinoma. Among them, basal-like type was the most glycolytic and acid-resistant phenotype.

Sayed-Ahmed MM, Hafez MM, Al-Shabanah OA, et al.
Increased expression of biological markers as potential therapeutic targets in Saudi women with triple-negative breast cancer.
Tumori. 2013 Jul-Aug; 99(4):545-54 [PubMed] Related Publications
AIMS AND BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2). Although TNBC represents only 15% of all types of breast cancer, it accounts for a large number of metastatic cases and deaths. Because of the high metastatic rate and both local and systemic recurrence associated with TNBC, extensive research efforts are actively looking for target therapies to effectively treat this aggressive disease. Accordingly, this study has been initiated to investigate the differential expression of biological markers in TNBC and non-TNBC Saudi women that might be utilized as potential targeted therapy and/or predict the sensitivity to currently available therapeutic regimens.
METHODS AND STUDY DESIGN: Two hundred formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues were selected and divided into 3 groups: benign breast tissues (20), TNBC tissues (80) and non-TNBC tissues (100). Expression of mRNA in FFPE tissues was analyzed using real-time polymerase chain reaction (RT-PCR) for the following genes: poly (ADP-ribose) polymerase 1 (PARP-1), topoisomerase 2A (TOPO-2A), vascular endothelial growth factor (VEGF), C-MYC, basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMP-2 and MMP-9), human epidermal growth factor 1 (HER1) and multidrug resistance (MDR) genes.
RESULTS: In the TNBC group, expression of PARP-1, TOPO-2A, HER1, C-MYC, VEGF, bFGF and MMP-2 showed a highly significant increase compared to the non-TNBC group.
CONCLUSIONS: The results of this study suggest that (1) TNBC patients will benefit more from TOPO-2A inhibitors as well as antiangiogenic and antimetastatic therapies; (2) inhibition of these target genes is emerging as one of the most exciting and promising targeted therapeutic strategies to treat TNBC in which the intended targets are DNA repair, tumor angiogenesis and metastasis.

Crowder SW, Horton LW, Lee SH, et al.
Passage-dependent cancerous transformation of human mesenchymal stem cells under carcinogenic hypoxia.
FASEB J. 2013; 27(7):2788-98 [PubMed] Free Access to Full Article Related Publications
Bone marrow-derived human mesenchymal stem cells (hMSCs) either promote or inhibit cancer progression, depending on factors that heretofore have been undefined. Here we have utilized extreme hypoxia (0.5% O2) and concurrent treatment with metal carcinogen (nickel) to evaluate the passage-dependent response of hMSCs toward cancerous transformation. Effects of hypoxia and nickel treatment on hMSC proliferation, apoptosis, gene and protein expression, replicative senescence, reactive oxygen species (ROS), redox mechanisms, and in vivo tumor growth were analyzed. The behavior of late passage hMSCs in a carcinogenic hypoxia environment follows a profile similar to that of transformed cancer cells (i.e., increased expression of oncogenic proteins, decreased expression of tumor suppressor protein, increased proliferation, decreased apoptosis, and aberrant redox mechanisms), but this effect was not observed in earlier passage control cells. These events resulted in accumulated intracellular ROS in vitro and excessive proliferation in vivo. We suggest a mechanism by which carcinogenic hypoxia modulates the activity of three critical transcription factors (c-MYC, p53, and HIF1), resulting in accumulated ROS and causing hMSCs to undergo cancer-like behavioral changes. This is the first study to utilize carcinogenic hypoxia as an environmentally relevant experimental model for studying the age-dependent cancerous transformation of hMSCs.

Song YH, Jeong SJ, Kwon HY, et al.
Ursolic acid from Oldenlandia diffusa induces apoptosis via activation of caspases and phosphorylation of glycogen synthase kinase 3 beta in SK-OV-3 ovarian cancer cells.
Biol Pharm Bull. 2012; 35(7):1022-8 [PubMed] Related Publications
Although ursolic acid isolated from Oldenlandia diffusa (Rubiaceae) was known to have anticancer activities in prostate, breast and liver cancers, the underlying mechanism of ursolic acid in ovarian cancer cells was not investigated so far. In the present study, the apoptotic mechanism of ursolic acid was elucidated in SK-OV-3 ovarian cancer cells by 2,3-bis(2-methoxy-4-nitro-5-sulphophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay, cell cycle analysis and Western blotting. Ursolic acid exerted cytotoxicity against SK-OV-3 and A2780 ovarian cancer cells with IC₅₀ of ca. 50 and 65 µM, respectively. Apoptotic bodies were observed in ursolic acid treated SK-OV-3 cells. Also, ursolic acid significantly increased ethidium homodimer stained cells and sub-G1 apoptotic portion in SK-OV-3 cells. Consistently, Western blotting revealed that ursolic acid effectively cleaved poly(ADP-ribose) polymerase (PARP), caspase-9 and -3, suppressed the expression of survival genes such as c-Myc, Bcl-x(L) and astrocyte elevated gene (AEG)-1, and upregulated phosphorylation of extracellular signal-regulated kinase (ERK) in SK-OV-3 cells. Interestingly, ursolic acid suppressed β-catenin degradation as well as enhanced phosphorylation of glycogen synthase kinase 3 beta (GSK 3β). Furthermore, GSK 3β inhibitor SB216763 blocked the cleavages of caspase-3 and PARP induced by ursolic acid and proteosomal inhibitor MG132 disturbed down-regulation of β-catenin, activation of caspase-3 and decreased mitochondrial membrane potential (MMP) induced by ursolic acid in SK-OV-3 cells. Overall, our findings suggest that ursolic acid induces apoptosis via activation of caspase and phosphorylation of GSK 3β in SK-OV-3 cancer cells as a potent anti-cancer agent for ovarian cancer therapy.

Ryan SL, Schwalbe EC, Cole M, et al.
MYC family amplification and clinical risk-factors interact to predict an extremely poor prognosis in childhood medulloblastoma.
Acta Neuropathol. 2012; 123(4):501-13 [PubMed] Related Publications
The MYC oncogenes are the most commonly amplified loci in medulloblastoma, and have previously been proposed as biomarkers of adverse disease prognosis by us and others. Here, we report focussed and comprehensive investigations of MYCC, MYCN and MYCL in an extensive medulloblastoma cohort (n = 292), aimed to define more precisely their biological significance and optimal clinical application to direct improved disease risk-stratification and individualisation of therapy. MYCC and MYCN expression elevations were multifactorial, associated with high-risk (gene amplification, large-cell/anaplastic pathology (LCA)) and favourable-risk (WNT/SHH molecular subgroups) disease features. Highly variable cellular gene amplification patterns underlay overall MYC copy number elevations observed in tumour biopsies; we used these alternative measures together to define quantitative methodologies and thresholds for amplification detection in routinely collected tumour material. MYCC and MYCN amplification, but not gain, each had independent prognostic significance in non-infants (≥3.0-16.0 years), but MYCC conferred a greater hazard to survival than MYCN when considered across this treatment group. MYCN's weaker group-wide survival relationship may be explained by its pleiotropic behaviour between clinical disease-risk groups; MYCN predicted poor prognosis in clinical high-risk (metastatic (M+) or LCA), but not standard-risk, patients. Extending these findings, survival decreased in proportion to the total number of independently significant high-risk features present (LCA, M+ or MYCC/MYCN amplification). This cumulative-risk model defines a patient group characterised by ≥2 independent risk-factors and an extremely poor prognosis (<15% survival), which can be identified straightforwardly using the reported MYC amplification detection methodologies alongside clinical assessments, enabling targeting for novel/intensified therapies in future clinical studies.

Díaz-Molina JP, Llorente JL, Vivanco B, et al.
Wnt-pathway activation in intestinal-type sinonasal adenocarcinoma.
Rhinology. 2011; 49(5):593-9 [PubMed] Related Publications
BACKGROUND: Intestinal-type sinonasal adenocarcinoma (ITAC) is an epithelial cancer of the sinonasal sinuses that shows histological similarity to colorectal cancer (CRC) and share chronic inflammation as a possible etiological factor. The Wnt-pathway is one of the most important tumourigenic pathways in CRC. The aim of this study was to investigate if the Wnt-pathway is activated in ITAC.
METHODOLOGY: Protein expression profiles of E-cadherin, β-catenin, c-myc and cyclin D1 were analysed by immunohistochemistry in 83 samples of ITAC, organized into tissue microarray blocks.
RESULTS: Nuclear β-catenin expression was observed in 31% of the cases and was twice as frequent in papillary/colonic ITAC compared to solid/mucinous subtypes. Loss of membranous β-catenin staining occurred in 24% and loss of membranous E-cadherin in 6% of the cases and this was more prominent in mucinous types. Strong c-myc and cyclin D1 expression was observed in 30% and 4% of the cases, respectively. Nuclear β-catenin expression was significantly related to poor clinical outcome, independent from established factors as tumour stage and histological type.
CONCLUSION: The presence of nuclear β-catenin in 31% of patients with ITACs indicated that in a subset of patients, the Wnt-pathway is active and conveys a worse prognosis.

Bayley JP, Devilee P
The Warburg effect in 2012.
Curr Opin Oncol. 2012; 24(1):62-7 [PubMed] Related Publications
PURPOSE OF REVIEW: A revival of interest in tumor metabolism is underway and here we discuss recent results with a focus on the central theme of the Warburg effect, aerobic glycolysis.
RECENT FINDINGS: The M2 tumor-specific isoform of pyruvate kinase has generated much interest, but it has now been reported that PKM2 is not specific to tumors. Despite this setback, the reciprocal regulation of PKM2, prolyl hydroxylase 3 and HIF-1 in a positive feedback loop shows that PKM2 is important to tumor metabolism. Hexokinase II was reported to be a crucial regulator of glycolysis in glioblastoma multiforme, and the importance of lactate dehydrogenase was underlined by evidence that a 'lactate-based dialog' exists between cancer cells and endothelial cells. A growing appreciation of the role of oncogenes and tumor suppressor genes in the Warburg effect was reflected in reports of the regulation of glutamine metabolism by p53, the role of c-Myc in the high glucose uptake of tumors, and the regulation of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) and ATP consumption by AKT. The sirtuins, SIRT3 and SIRT6, were also shown to play central roles in aerobic glycolysis and other aspects of tumor metabolism.
SUMMARY: The results discussed illustrate the growing integration of the previously distinct fields of molecular biological and metabolic cancer research and show that this synergy is beginning to yield a more complete and comprehensive understanding of the tumor cell.

Möröy T, Saba I, Kosan C
The role of the transcription factor Miz-1 in lymphocyte development and lymphomagenesis-Binding Myc makes the difference.
Semin Immunol. 2011; 23(5):379-87 [PubMed] Related Publications
The Myc interacting zinc finger protein 1 (Miz-1) is a BTB/POZ domain containing transcription factor that can function as an activator or repressor depending on its binding partners. In a complex with co-factors such as nuclophosmin or p300, Miz-1 stimulates transcription of genes that encode regulators of cell cycle progression such as p21(Cip1) or p15(Ink4b) or inhibitors of apoptosis such as Bcl-2. In contrast, Miz-1 becomes a transcriptional repressor when it binds to c-Myc or Bcl-6, which replace nucleophosmin or p300. During lymphocyte development, Miz-1 functions as a regulator of the IL-7 signaling pathway at very early steps in the bone marrow and thymus. When the IL-7 receptor (IL-7R) recognizes its cognate cytokine, a cascade of events is initiated that involves the recruitment of janus kinases (JAK) to the cytoplasmic part of the IL-7R, the phosphorylation of Stat5, its dimerization and relocation to the nucleus, enabling a transcriptional programming that governs commitment, survival and proliferation of lymphoid lineage cells. Miz-1 is critical in this signal transduction pathway, since it controls the expression of Socs1, an inhibitor of JAKs and thus of Stat5 activation and Bcl-2 expression. A lack of Miz-1 blocks IL-7 mediated signaling, which is detrimental for early B- and T-lymphoid development. These functions of Miz-1 during early lymphocyte development are c-Myc-independent. In contrast, when c-Myc is constitutively over-expressed, for instance during c-Myc induced lymphomagenesis, the interaction between Miz-1 and c-Myc becomes important and critical for the initiation and maintenance of c-Myc-dependent lymphoid malignancies.

Mertz JA, Conery AR, Bryant BM, et al.
Targeting MYC dependence in cancer by inhibiting BET bromodomains.
Proc Natl Acad Sci U S A. 2011; 108(40):16669-74 [PubMed] Free Access to Full Article Related Publications
The MYC transcription factor is a master regulator of diverse cellular functions and has been long considered a compelling therapeutic target because of its role in a range of human malignancies. However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein-DNA interactions. Here, we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. MYC transcriptional suppression was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G(1) arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from cell cycle arrest and growth suppression by BET inhibitors. MYC suppression was accompanied by deregulation of the MYC transcriptome, including potent reactivation of the p21 tumor suppressor. Treatment with a BET inhibitor resulted in significant antitumor activity in xenograft models of Burkitt's lymphoma and acute myeloid leukemia. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer.

Zhu W, Cai MY, Tong ZT, et al.
Overexpression of EIF5A2 promotes colorectal carcinoma cell aggressiveness by upregulating MTA1 through C-myc to induce epithelial-mesenchymaltransition.
Gut. 2012; 61(4):562-75 [PubMed] Related Publications
BACKGROUND AND AIMS: The authors have previously isolated a putative oncogene, eukaryotic initiation factor 5A2 (EIF5A2) from 3q26. In this study, EIF5A2 was characterised for its role in colorectal carcinoma (CRC) aggressiveness and underlying molecular mechanisms.
METHODS: The expression dynamics of EIF5A2 were examined by immunohistochemistry in a cohort of carcinomatous and non-neoplastic colorectal tissues and cells. A series of in-vivo and in-vitro assays was performed to elucidate the function of EIF5A2 in CRC and its underlying mechanisms.
RESULTS: The overexpression of EIF5A2 was examined by immunohistochemistry in 102/229 (44.5%) CRC patients, and it was significantly correlated with tumour metastasis and determined to be an independent predictor of shortened survival (p<0.05). Ectopic overexpression of EIF5A2 in CRC cells enhanced cell motility and invasion in vitro and tumour metastasis in vivo, and induced epithelial-mesenchymal transition (EMT). The depletion of EIF5A2 expression prevented CRC cell invasiveness and inhibited EMT. Importantly, the metastasis-associated protein 1 (MTA1) gene was identified as a potential downstream target of EIF5A2 in CRC cells, and knockdown of MTA1 eliminated the augmentation of carcinoma cell migration, invasion and EMT by ectopic EIF5A2. The overexpression of EIF5A2 in CRC cells substantially enhanced the enrichment of c-myc on the promoter of MTA1, and MTA1 upregulation by EIF5A2 was partly dependent on c-myc.
CONCLUSION: The data suggest that EIF5A2 plays an important oncogenic role in CRC aggressiveness by the upregulation of MTA1 to induce EMT, and EIF5A2 could be employed as a novel prognostic marker and/or effective therapeutic target for CRC.

Wen G, Hong M, Li B, et al.
Transforming growth factor-β-induced protein (TGFBI) suppresses mesothelioma progression through the Akt/mTOR pathway.
Int J Oncol. 2011; 39(4):1001-9 [PubMed] Free Access to Full Article Related Publications
As an uncommon cancer, mesothelioma is very hard to treat with a low average survival rate owing to its usual late detection and being highly invasive. The link between asbestos exposure and the development of mesothelioma in humans is unequivocal. TGFBI, a secreted protein that is induced by transforming growth factor-β in various human cell types, has been shown to be associated with tumorigenesis in various types of tumors. It has been demonstrated that TGFBI expression is markedly suppressed in asbestos-induced tumorigenic cells, while an ectopic expression of TGFBI significantly suppresses tumorigenicity and progression in human bronchial epithelial cells. In order to delineate a potential role of TGFBI in mediating the molecular events that occur in mesothelioma tumorigenesis, we generated stable TGFBI knockdown mutants from the mesothelium cell line Met-5A by using an shRNA approach, and secondly created ectopic TGFBI overexpression mutants from the mesothelioma cell line H28 in which TGFBI is absent. We observed that in the absence of TGFBI, the knockdown mesothelial and mesothelioma cell lines exhibited an elevated proliferation rate, enhanced plating efficiency, increased anchorage-independent growth, as well as an increased cellular protein synthesis rate as compared with their respective controls. Furthermore, cell cycle regulatory proteins c-myc/cyclin D1/phosphor-Rb were upregulated; a more active PI3K/Akt/mTOR signaling pathway was also detected in TGFBI-depleted cell lines. These findings suggest that TGFBI may repress mesothelioma tumorigenesis and progression via the PI3K/Akt signaling pathway.

Sun T, Wang C, Xing J, Wu D
miR-429 modulates the expression of c-myc in human gastric carcinoma cells.
Eur J Cancer. 2011; 47(17):2552-9 [PubMed] Related Publications
AIM: MicroRNAs (miRNAs) are a recently discovered class of small non-coding RNAs that regulate gene expression and may contribute to the development and progression of many cancers. In this study, our goal was to investigate the regulation of miR-429 in gastric cancer and explored the mechanism/s by which it influenced pathogenesis of gastric cancer.
METHODS: We used real-time reverse transcriptase-polymerase chain reaction to quantify the expression level of miR-429 in 52 gastric cancer tissues and their paracancerous tissues. Bioinformatics was used to predict downstream target genes of miR-429. SGC-7901 gastric cancer cells were transfected with miR-429 mimics and endogenous c-myc expression was detected by western blots. We performed functional assays using the 3'UTR of the c-myc gene as a miR-429 target in a luciferase reporter assay system.
RESULTS: We showed that miR-429 was downregulated in human gastric carcinoma tissue and in SGC-7901 cells. Cell viability, proliferation and attachment were inhibited in miR-429-transfected cells. miR-429 significantly downregulated endogenous c-myc expression in SGC-7901 cells. Action of miR/429 on c-myc 3'UTR was confirmed. The levels of miR-429 in tumour tissue of patients with lymph node metastasis were significantly lower than in those without lymph node metastasis.
CONCLUSIONS: Our results suggested that miR-429 played a role in the pathogenesis of gastric carcinoma and may function as a recessive cancer gene. c-myc is an important miR-429 target gene.

Shaw EJ, Haylock B, Husband D, et al.
Gene expression in oligodendroglial tumors.
Cell Oncol (Dordr). 2011; 34(4):355-67 [PubMed] Related Publications
BACKGROUND: Oligodendroglial tumors with 1p/19q loss are more likely to be chemosensitive and have longer survival than those with intact 1p/19q, but not all respond to chemotherapy, warranting investigation of the biological basis of chemosensitivity.
METHODS: Gene expression profiling was performed using amplified antisense RNA from 28 oligodendroglial tumors treated with chemotherapy [26 serial stereotactic biopsy, 2 resection]. Expression of differentially expressed genes was validated by real-time PCR.
RESULTS: Unsupervised hierarchical clustering showed clustering of multiple samples from the same case in 14/17 cases and identified subgroups associated with tumor grade and 1p/19q status. 176 genes were differentially expressed, 164 being associated with 1p/19q loss (86% not on 1p or 19q). 94 genes differed between responders and non-responders to chemotherapy; 12 were not associated with 1p/19q loss. Significant differential expression was confirmed in 11/13 selected genes. Novel genes associated with response to therapy included SSBP2, GFRA1, FAP and RASD1. IQGAP1, INA, TGIF1, NR2F2 and MYCBP were differentially expressed in oligodendroglial tumors with 1p/19q loss.
CONCLUSION: Gene expression profiling using serial stereotactic biopsies indicated greater homogeneity within tumors than between tumors. Genes associated with 1p/19q status or response were identified warranting further elucidation of their role in oligodendroglial tumors.

Cho YJ, Tsherniak A, Tamayo P, et al.
Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome.
J Clin Oncol. 2011; 29(11):1424-30 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors.
PATIENTS AND METHODS: We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization-based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets.
RESULTS: Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event-free and overall survivals.
CONCLUSION: Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.

Shaw EJ, Haylock B, Husband D, et al.
Gene expression in oligodendroglial tumors.
Anal Cell Pathol (Amst). 2010; 33(2):81-94 [PubMed] Related Publications
BACKGROUND: Oligodendroglial tumors with 1p/19q loss are more likely to be chemosensitive and have longer survival than those with intact 1p/19q, but not all respond to chemotherapy, warranting investigation of the biological basis of chemosensitivity.
METHODS: Gene expression profiling was performed using amplified antisense RNA from 28 oligodendroglial tumors treated with chemotherapy (26 serial stereotactic biopsy, 2 resection). Expression of differentially expressed genes was validated by real-time PCR.
RESULTS: Unsupervised hierarchical clustering showed clustering of multiple samples from the same case in 14/17 cases and identified subgroups associated with tumor grade and 1p/19q status. 176 genes were differentially expressed, 164 being associated with 1p/19q loss (86% not on 1p or 19q). 94 genes differed between responders and non-responders to chemotherapy; 12 were not associated with 1p/19q loss. Significant differential expression was confirmed in 11/13 selected genes. Novel genes associated with response to therapy included SSBP2, GFRA1, FAP and RASD1. IQGAP1, INA, TGIF1, NR2F2 and MYCBP were differentially expressed in oligodendroglial tumors with 1p/19q loss.
CONCLUSION: Gene expression profiling using serial stereotactic biopsies indicated greater homogeneity within tumors than between tumors. Genes associated with 1p/19q status or response were identified warranting further elucidation of their role in oligodendroglial tumors.

Xiong J, Du Q, Liang Z
Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein.
Oncogene. 2010; 29(35):4980-8 [PubMed] Related Publications
Oncogenic c-Myc has been described to modulate the expression of a subset of microRNAs (miRNAs), which include miR-22; however, the mechanism through which a miRNA controls c-Myc activity remains unclear. Here we report a novel anti-c-Myc function mediated by miR-22. Ectopically expressed miR-22 inhibited cell proliferation and anchorage-independent growth of human cancer cell lines. Microarray screening and western analyses revealed that miR-22 repressed the c-Myc-binding protein MYCBP, a positive regulator of c-Myc. Consistent with this, reporter assays showed that miR-22-mediated MYCBP gene suppression largely depends on the conserved miR-22 target site within the MYCBP 3'-untranslational region (3'UTR), implying that MYCBP mRNA is a direct miR-22 target. Depletion of MYCBP using small interfering RNA (siRNA) recapitulated the miR-22-induced anti-growth effect on tumor cells, whereas ectopically expressed MYCBP rescued cells from the growth suppression mediated by miR-22. Moreover, repression of MYCBP by miR-22 downregulated a panel of E-box-containing c-Myc target genes. Our results suggest that miR-22 acts as a tumor suppressor through direct repression of MYCBP expression and subsequent reduction of oncogenic c-Myc activities. As c-Myc inhibits the expression of miR-22, we propose a novel positive feedback loop formed by oncogenic c-Myc to accelerate cell proliferation by suppressing miR-22, a potent inhibitor of MYCBP.

Wang HB, Wang XW, Zhou G, et al.
PinX1 inhibits telomerase activity in gastric cancer cells through Mad1/c-Myc pathway.
J Gastrointest Surg. 2010; 14(8):1227-34 [PubMed] Related Publications
INTRODUCTION: The aim of this study was to investigate the role of Mad1/c-Myc in telomerase regulation in gastric cancer cells in order to gain insight into telomerase activity and to evaluate PinX1 as a putative inhibitor of gastric cancer.
METHODS: PinX1 and PinX1siRNA eukaryotic expression vectors were constructed by recombinant technology and transfected into gastric carcinoma cells using Lipofectamine 2000. Telomerase activity was measured by the telomeric repeat amplification protocol. Apoptosis of gastric cancer cells was analyzed by flow cytometry and transmission electron microscopy. Reverse transcription-polymerase chain reaction and Western blotting were used to assess the expression levels of PinX1 and Mad1/c-Myc.
RESULTS: We found that PinX1-negative gastric cancer cells showed significantly higher telomerase activity than did the PinX1-postive cells. PinX1-transfection reduced telomerase activity in PinX1-negative gastric cancer cells and exhibited an upregulation of Mad1 and downregulation of c-Myc expression. Pinx1 RNAi treatment led to downregulation of Mad1 and upregulation of c-Myc.
CONCLUSION: Suppression of telomerase activity mediated by PinX1 is involved in the Mad1/c-Myc pathway.

Duhagon MA, Hurt EM, Sotelo-Silveira JR, et al.
Genomic profiling of tumor initiating prostatospheres.
BMC Genomics. 2010; 11:324 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The cancer stem cell (CSC) hypothesis proposes that a population of tumor cells bearing stem cell properties is responsible for the origin and maintenance of tumors. Normal and cancer stem cells possess the ability to grow in vitro as self-renewing spheres, but the molecular basis of this phenotype remains largely unknown. We intended to establish a comprehensive culture system to grow prostatospheres (PSs) from both cancer cell lines and patient tumors. We then used gene expression microarrays to gain insight on the molecular pathways that sustain the PS tumor initiating cell (TIC) phenotype.
RESULTS: Traditional stem cell medium (SCM) supplemented with KnockoutSR (KO) allows the propagation of monoclonal PSs from cell lines and primary cells. PSs display gene expression and tumorigenicity hallmarks of TICs. Gene expression analysis defined a gene signature composed of 66 genes that characterize LNCaP and patient PSs. This set includes novel prostate TIC growth factors (NRP1, GDF1, JAG1), proteins implicated in cell adhesion and cytoskeletal maintenance, transcriptional regulators (MYCBP, MYBL1, ID1, ID3, FOS, ELF3, ELF4, KLF2, KLF5) and factors involved in protein biosynthesis and metabolism. Meta-analysis in Oncomine reveals that some of these genes correlate with prostate cancer status and/or progression. Reporter genes and inhibitors indicate that the Notch pathway contributes to prostatosphere growth.
CONCLUSIONS: We have developed a model for the culture of PSs, and provide a genomic profile that support CSCs identity. This signature identifies novel markers and pathways that are predicted to correlate with prostate cancer evolution.

Bae KM, Su Z, Frye C, et al.
Expression of pluripotent stem cell reprogramming factors by prostate tumor initiating cells.
J Urol. 2010; 183(5):2045-53 [PubMed] Free Access to Full Article Related Publications
PURPOSE: We identified a discrete population of stem cell-like tumor cells expressing 5 essential transcription factors required to reprogram pluripotency in prostate tumor cell lines and primary prostate cancer tissue.
MATERIALS AND METHODS: DU145 and PC3 human prostate cancer cell lines (ATCC), tumor tissue from patients with prostate cancer and normal prostate tissue were evaluated for the reprogramming factors OCT3/4 (Cell Signaling Technology), SOX2, Klf4 (Santa Cruz Biotechnology, Santa Cruz, California), Nanog (BioLegend) and c-Myc (Cell Signaling) by semiquantitative reverse transcriptase-polymerase chain reaction, histological and immunohistochemical analysis. Stem cell-like tumor cells were enriched by flow cytometric cell sorting using E-cadherin (R&D Systems) as a surface marker, and soft agar, spheroid and tumorigenicity assays to confirm cancer stem cell-like characteristics.
RESULTS: mRNA expression of transcription factors OCT3/4 and SOX2 highly correlated in primary prostate tumor tissue samples. The number of OCT3/4 or SOX2 expressing cells was significantly increased in prostate cancer tissue compared to that in normal prostate or benign prostate hyperplasia tissue (p <0.05). When isolated from the DU145 and PC3 prostate cancer cell lines by flow cytometry, stem cell-like tumor cells expressing high OCT3/4 and SOX2 levels showed high tumorigenicity in immunodeficient mice. In vivo growth of the parental DU145 and PC3 prostate cancer cell lines was inhibited by short hairpin RNA knockdown of OCT3/4 or SOX2.
CONCLUSIONS: Data suggest that prostate tumor cells expressing pluripotent stem cell transcription factors are highly tumorigenic. Identifying such cells and their importance in prostate cancer growth could provide opportunities for novel targeting strategies for prostate cancer therapy.

Singh AD, Tubbs R, Biscotti C, et al.
Chromosomal 3 and 8 status within hepatic metastasis of uveal melanoma.
Arch Pathol Lab Med. 2009; 133(8):1223-7 [PubMed] Related Publications
CONTEXT: Several studies have evaluated clinical, histopathologic, cytogenetic, and molecular prognostic variables in uveal melanoma. However, it is not known whether the primary tumor cells maintain these aggressive attributes at the metastatic sites.
OBJECTIVE: To determine the status of chromosomes 3 and 8q and c-myc amplification using fluorescence in situ hybridization on hepatic metastatic lesions of primary uveal melanoma.
DESIGN: Ten patients with uveal melanoma with needle core biopsy-confirmed hepatic metastasis. Representative paraffin blocks were selected based on review of hematoxylin-eosin-stained sections. Fluorescence in situ hybridization was performed for detection of monosomy 3 and amplification at the 8q24 MYC locus using standard methods. The tricolor chromosome enumeration probe 8 (CEP8)/IGH/MYC and the Urovysion probe consisting of CEP3, CEP7, CEP17, and 9P21 probes were used. A total of 200 interphase cells were scored.
RESULTS: Hepatic metastasis was confirmed in each case by needle core biopsy. Fluorescence in situ hybridization analysis revealed chromosome 3 monosomy in 5 of the 8 cases that could be satisfactorily evaluated. Aneusomy of chromosome 8 was observed in 2 cases. MYC amplification was observed in 5 samples. In a single case where the primary tumor was treated by enucleation, the chromosomal monosomy 3 and aneusomy of chromosome 8 were present both in the primary tumor and its hepatic metastatic lesion.
CONCLUSIONS: The presence of cytogenetic changes within the metastatic lesions confirms that chromosome 3 monosomy and aneusomy of chromosome 8 are not just markers of metastatic potential of the primary tumor but are also present within the hepatic metastatic lesions.

Zeng H, Wu M, Botnen JH
Methylselenol, a selenium metabolite, induces cell cycle arrest in G1 phase and apoptosis via the extracellular-regulated kinase 1/2 pathway and other cancer signaling genes.
J Nutr. 2009; 139(9):1613-8 [PubMed] Related Publications
Methylselenol has been hypothesized to be a critical selenium (Se) metabolite for anticancer activity in vivo, and our previous study demonstrated that submicromolar methylselenol generated by incubating methionase with seleno-l-methionine inhibits the migration and invasive potential of HT1080 tumor cells. However, little is known about the association between cancer signal pathways and methylselenol's inhibition of tumor cell invasion. In this study, we demonstrated that methylselenol exposure inhibited cell growth and we used a cancer signal pathway-specific array containing 15 different signal transduction pathways involved in oncogenesis to study the effect of methylselenol on cellular signaling. Using real-time RT-PCR, we confirmed that cellular mRNA levels of cyclin-dependent kinase inhibitor 1C (CDKN1C), heme oxygenase 1, platelet/endothelial cell adhesion molecule, and PPARgamma genes were upregulated to 2.8- to 5.7-fold of the control. BCL2-related protein A1, hedgehog interacting protein, and p53 target zinc finger protein genes were downregulated to 26-52% of the control, because of methylselenol exposure. These genes are directly related to the regulation of cell cycle and apoptosis. Methylselenol increased apoptotic cells up to 3.4-fold of the control and inhibited the extracellular-regulated kinase 1/2 (ERK1/2) signaling and cellular myelocytomatosis oncogene (c-Myc) expression. Taken together, our studies identify 7 novel methylselenol responsive genes and demonstrate that methylselenol inhibits ERK1/2 pathway activation and c-Myc expression. The regulation of these genes is likely to play a key role in G1 cell cycle arrest and apoptosis, which may contribute to the inhibition of tumor cell invasion.

Weber A, Kristiansen I, Johannsen M, et al.
The FUSE binding proteins FBP1 and FBP3 are potential c-myc regulators in renal, but not in prostate and bladder cancer.
BMC Cancer. 2008; 8:369 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The three far-upstream element (FUSE) binding proteins (FBP1, FBP2, and FBP3) belong to an ancient family of single-stranded DNA binding proteins which are required for proper regulation of the c-myc proto-oncogene. Whereas it is known that c-myc alterations play a completely different role in various carcinomas of the urogenital tract, the relevance of FBPs is unclear.
METHODS: FBP1, FBP3 and c-myc expression was studied in 105 renal cell, 95 prostate and 112 urinary bladder carcinomas by immunohistochemistry using tissue microarrays.
RESULTS: High rates of FBP1 and FBP3 expression were observed in all cancer types. There was a concomitant up-regulation of FBP1 and FBP3 in renal cell and prostate carcinomas (p < 0.001 both). C-myc expression was detectable in 21% of prostate, 30% of renal and 34% of urothelial carcinomas. Interestingly, strong FBP1 and FBP3 expression was associated with c-myc up-regulation in clear cell renal cell carcinomas (p < 0.001 and 0.09 resp.), but not in bladder or prostate cancer.
CONCLUSION: The correlation between FBP1/FBP3, c-myc and high proliferation rate in renal cell carcinoma provides strong in vivo support for the suggested role of FBP1 and FBP3 as activators of c-myc. The frequent up-regulation of FBP1 and FBP3 in urothelial and prostate carcinoma suggests that FBPs also have an important function in gene regulation of these tumors.

Barnes RO, Parisien M, Murphy LC, Watson PH
Influence of evolution in tumor biobanking on the interpretation of translational research.
Cancer Epidemiol Biomarkers Prev. 2008; 17(12):3344-50 [PubMed] Related Publications
PURPOSE: Translational cancer research increasingly relies on human tissue biospecimens and this has coincided with a shift in tissue biobanking approach. Newer biobanks (post year 2000) deploy standard operating procedures to reduce variability around biospecimen collection. Because current translational research is based on pre-2000 and post-2000 era biospecimens, we consider whether the collection era may influence gene expression data.
DESIGN: We compared the range of breast tumor collection times from pre-2000 and post-2000 era biobanks and compared estrogen receptor (ER) protein expression with collection time. We then collected 10 breast tumor biospecimens under a standardized protocol and examined whether the expression of c-myc and ER was influenced by storage on ice < or = 24 hours.
RESULTS: The range of collection times achieved at a pre-2000 versus post-2000 era biobank differed. Thirty-two percent of biospecimens were cryopreserved within 30 minutes at the pre-2000 era biobank versus 76% at the post-2000 era biobank. Collection time and ER protein level was inversely correlated (r = -0.19, P = 0.025; n = 137). We observed a wide range in initial c-myc and ER mRNA levels (50- versus 130-fold). Although mRNA levels of both genes declined with increasing collection time, the rate of change differed because c-myc was significantly reduced after 24 hours (mean reduction to 79% of initial) versus ER (94% of initial).
CONCLUSION: The overall shift in biobanking around the year 2000 is reflected in the ranges of collection times associated with pre-2000 and post-2000 era biobanks. Because collection time can differentially alter gene expression, the biospecimen collection era should be considered in gene expression studies.

Fujiwara SI, Yamashita Y, Nakamura N, et al.
High-resolution analysis of chromosome copy number alterations in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified, with single nucleotide polymorphism-typing microarrays.
Leukemia. 2008; 22(10):1891-8 [PubMed] Related Publications
Angioimmunoblastic T-cell lymphoma (AILT) and peripheral T-cell lymphoma, unspecified (PTCL-u) are relatively frequent subtypes of T- or natural killer cell lymphoma. To characterize the structural anomalies of chromosomes associated with these disorders, we here determined chromosome copy number alterations (CNAs) and loss of heterozygosity (LOH) at >55,000 single nucleotide polymorphism loci for clinical specimens of AILT (n=40) or PTCL-u (n=33). Recurrent copy number gain common to both conditions was detected on chromosomes 8, 9 and 19, whereas common LOH was most frequent for a region of chromosome 2. AILT- or PTCL-u-specific CNAs or LOH were also identified at 21 regions, some spanning only a few hundred base pairs. We also identified prognosis-related CNAs or LOH by several approaches, including Cox's proportional hazard analysis. Among the genes that mapped to such loci, a poor prognosis was linked to overexpression of CARMA1 at 7p22 and of MYCBP2 at 13q22, with both genes being localized within regions of frequent copy number gain. For a frequent LOH region at 2q34, we also identified IKAROS family zinc-finger 2 cDNAs encoding truncated proteins. Our data indicate that AILT and PTCL-u consist of heterogeneous subgroups with distinct transforming genetic alterations.

Wang Y, Liu S, Zhu H, et al.
FRAT1 overexpression leads to aberrant activation of beta-catenin/TCF pathway in esophageal squamous cell carcinoma.
Int J Cancer. 2008; 123(3):561-8 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with a poor prognosis. Although aberrant activation of beta-catenin/T-cell factor (TCF) pathway has been observed in ESCC, mechanisms underlying this phenomenon remain unknown. Frequently rearranged in advanced T-cell lymphomas-1 (FRAT1), overexpressed in some ESCC lines, is a positive regulator of beta-catenin/TCF pathway. However, little is known about the molecular relationship between FRAT1 and beta-catenin/TCF in ESCC. In this study, we analyzed freshly resected ESCC specimens and demonstrated that FRAT1 was overexpressed in approximately 74% of tumor samples compared with matched normal tissue. Overexpression of FRAT1 significantly promoted esophageal cancer cells growth, whereas suppression of FRAT1 level by RNAi markedly inhibited their growth. In addition, FRAT1 overexpression induced the nuclear accumulation of beta-catenin and promoted the transcriptional activity of beta-catenin/TCF. These effects were reversed by coexpression of GSK 3beta or DeltaN TCF4. Furthermore, accumulation of beta-catenin was correlated with FRAT1 overexpression in ESCC and the basal layer of normal esophageal epithelium. Finally, continued expression of c-Myc is necessary and sufficient for maintenance of the growth state in cells expressing FRAT1. Taken together, these results support the novel hypothesis that aberrant activation of beta-catenin/TCF pathway in esophageal cancer appears to be due to upstream events such as FRAT1 overexpression, and c-Myc may be an important element in oncogenesis of human ESCC induced by FRAT1.

Ellsworth RE, Ellsworth DL, Patney HL, et al.
Genomic alterations associated with early stages of breast tumor metastasis.
Ann Surg Oncol. 2008; 15(7):1989-95 [PubMed] Related Publications
BACKGROUND: Molecular studies suggest that acquisition of metastatic potential occurs early in the development of breast cancer; mechanisms by which cells disseminate from the primary carcinomas and successfully colonize foreign tissues are, however, largely unknown. Thus, we examined levels and patterns of chromosomal alterations in primary breast tumors from node-negative (n = 114) and node-positive (n = 115) patients to determine whether specific genomic changes are associated with tumor metastasis.
METHODS: Fifty-two genetic markers representing 26 chromosomal regions commonly altered in breast cancer were examined in laser microdissected tumor samples to assess levels and patterns of allelic imbalance (AI). Real time-PCR (RT-PCR) was performed to determine expression levels of candidate genes. Data was analyzed using exact unconditional and Student's t-tests with significance values of P < 0.05 and P < 0.002 used for the clinicopathological and genomic analyses, respectively.
RESULTS: Overall levels of AI in primary breast tumors from node-negative (20.8%) and node-positive (21.9%) patients did not differ significantly (P = 0.291). When data were examined by chromosomal region, only chromosome 8q24 showed significantly higher levels (P < 0.0005) of AI in node-positive primary tumors (23%) versus node-negative samples (6%). c-MYC showed significantly higher levels of gene expression in primary breast tumors from patients with lymph node metastasis.
CONCLUSIONS: Higher frequencies of AI at chromosome 8q24 in patients with positive lymph nodes suggest that genetic changes in this region are important to the process of metastasis. Because overexpression of c-MYC has been associated with cellular dissemination as well as development of the premetastatic niche, alterations of the 8q24 region, including c-MYC, may be key determinants in the development of lymph node metastasis.

Wong DJ, Liu H, Ridky TW, et al.
Module map of stem cell genes guides creation of epithelial cancer stem cells.
Cell Stem Cell. 2008; 2(4):333-44 [PubMed] Free Access to Full Article Related Publications
Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial. Here, we construct a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells, and human cancers. This map reveals two predominant gene modules that distinguish ESCs and adult tissue stem cells. The ESC-like transcriptional program is activated in diverse human epithelial cancers and strongly predicts metastasis and death. c-Myc, but not other oncogenes, is sufficient to reactivate the ESC-like program in normal and cancer cells. In primary human keratinocytes transformed by Ras and I kappa B alpha, c-Myc increases the fraction of tumor-initiating cells by 150-fold, enabling tumor formation and serial propagation with as few as 500 cells. c-Myc-enhanced tumor initiation is cell-autonomous and independent of genomic instability. Thus, activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristic of cancer stem cells.

Koldehoff M, Zakrzewski JL, Klein-Hitpass L, et al.
Gene profiling of growth factor independence 1B gene (Gfi-1B) in leukemic cells.
Int J Hematol. 2008; 87(1):39-47 [PubMed] Related Publications
To investigate the molecular effects of growth factor independence 1B (Gfi-1B), a transcription factor essential for the development of hematopoietic cells and differentiation of erythroid and megakaryocytic lineages, the naturally Gfi-1B overexpressing cell line K562 was cultured in the presence of Gfi-1B target-specific small interfering RNA (siRNA). SiRNA treatment significantly knocked down Gfi-1B expression with an efficiency of nearly 90%. Analysis of the siRNA silencing protocol by colony-forming units ensured that it was not cytotoxic. Samples from Gfi-1B overexpressing cells and cells with knocked-down Gfi-1B were analyzed by oligonucleotide microarray technology and based upon rigorous statistical analysis of the data; relevant genes were chosen for confirmation by reserve transcriptase-polymerase chain reaction, including MYC/MYCBP and CDKN1A. Interestingly, transcripts within components of the signalling cascade of immune cells (PLD1, LAMP1, HSP90, IL6ST), of the tyrosine kinase pathway (TPR, RAC3) and of the transcription factors (RAC3, CEP290, JEM-1, ATR, MYC, SMC3, RARA, RBBP6) were found to be differentially expressed in Gfi-1B overexpressing cells compared to controls. Individual genes such as ZDHHC17, DMXL1, ZNF292 were found to be upregulated in Gfi-1B overexpressing cells. In addition, down-regulated transcripts showed cell signaling transcripts for several chemokine gene members including GNAL, CXCL5, GNL3L, GPR65, TMEM30, BCL11B and transcription factors (GTF2H3, ATXN3). In conclusion, several essential cell signalling factors, as well as transcriptional and post-translational regulation genes were differentially expressed in cells that overexpressed Gfi-1B compared to control cells with knocked-down Gfi-1B. Our data indicate that Gfi-1B signalling is important for commitment and maturation of hematopoietic cell populations.

Kokkonen N, Ulibarri IF, Kauppila A, et al.
Hypoxia upregulates carcinoembryonic antigen expression in cancer cells.
Int J Cancer. 2007; 121(11):2443-50 [PubMed] Related Publications
Carcinoembryonic antigen (CEA, ceacam5) is an important tumor-associated antigen with reported roles, e.g., in immunological defense, cell adhesion, cell survival and metastasis. Its overexpression in cancer cells is known to involve transcriptional activation of the CEA gene, but the underlying molecular details remain unclear. Here, we show that hypoxia and intracellular alkalinization, 2 factors commonly found in solid tumors, increase CEA protein expression in breast (MCF-7) and colorectal (CaCo-2 and HT-29) cancer cells. The increase was comparable (2-3-fold) to that observed in colorectal carcinomas in vivo. CEA promoter analyses further revealed that this upregulation involves a known binding site for HIF-1 transcription factor (5'-ACGTG-3') within one of the CEA promoter's positive regulatory elements (the FP1 site; the E-box). Accordingly, deletion or targeted mutagenesis of this motif rendered the CEA promoter unresponsive to hypoxia. Our chromatin immunoprecipitation data confirmed that endogenous HIF-1alpha binds to the CEA promoter in hypoxic cells but not in normoxic cells. Moreover, overexpression of the hypoxia-inducible factor (HIF-1alpha) was sufficient to increase CEA protein expression in the cells. In contrast, c-Myc, which is known to bind to the overlapping E-box, did not potentiate HIF-1alpha-induced CEA expression. CEA overexpression in vivo was also found to coincide with the expression of carbonic anhydrase IX, a well-known hypoxia marker. Collectively, these results define CEA as a hypoxia-inducible protein and suggest an important role for the tumor microenvironmental factors in CEA overexpression during tumorigenesis.

Kim SJ, Lee HS, Shin JH, et al.
Preferentially enhanced gene expression from a synthetic human telomerase reverse transcriptase promoter in human cancer cells.
Oncol Rep. 2006; 16(5):975-9 [PubMed] Related Publications
Although the human telomerase reverse transcriptase (hTERT) promoter can regulate cancer-specific genes, it is generally too weak to be effective. We therefore attempted to improve the potency of synthetic hTERT promoters by fusing the core element (E) of the hTERT promoter (H) and the tripartite leader sequence (T) from human adenovirus 5 in a combinatorial manner. To determine the potential as cancer-specific promoters, we measured luciferase activity driven by the chimeric hTERT promoters in human cancer cells. Among various constructs, the E3-H-T promoter induced the strongest luciferase activity in all the tested cancer cells. SK-Hep1 and Hela cells experienced 1000- and 11-fold higher expression than the basic hTERT promoter, respectively. Relative to the SV40 universal promoter, the E3-H-T promoter led to higher levels of gene expression. Using EMSA, we found that the hTERT enhancer region was specifically bound to c-Myc and Sp1. Thus, the data suggest that the E3-H-T promoter with up-regulated cancer-specific gene expression could be useful in cancer gene therapy.

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