FABP7

Gene Summary

Gene:FABP7; fatty acid binding protein 7
Aliases: MRG, BLBP, FABPB, B-FABP
Location:6q22.31
Summary:The gene encodes a small, highly conserved cytoplasmic protein that bind long-chain fatty acids and other hydrophobic ligands. The encoded protein is important in the establishment of the radial glial fiber in the developing brain. Alternative splicing and promoter usage results in multiple transcript variants encoding different isoforms. Pseudogenes of this gene are found on multiple chromosomes. [provided by RefSeq, Jan 2016]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:fatty acid-binding protein, brain
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 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.

Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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

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

Latest Publications: FABP7 (cancer-related)

Panaccione A, Chang MT, Carbone BE, et al.
NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem-Like Cells in Adenoid Cystic Carcinoma.
Clin Cancer Res. 2016; 22(8):2083-95 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
PURPOSE: Although the existence of cancer stem cells (CSC) in adenoid cystic carcinoma (ACC) has been proposed, lack of assays for their propagation and uncertainty about molecular markers prevented their characterization. Our objective was to isolate CSC from ACC and provide insight into signaling pathways that support their propagation.
EXPERIMENTAL DESIGN: To isolate CSC from ACC and characterize them, we used ROCK inhibitor-supplemented cell culture, immunomagnetic cell sorting, andin vitro/in vivoassays for CSC viability and tumorigenicity.
RESULTS: We identified in ACC CD133-positive CSC that expressed NOTCH1 and SOX10, formed spheroids, and initiated tumors in nude mice. CD133(+)ACC cells produced activated NOTCH1 (N1ICD) and generated CD133(-)cells that expressed JAG1 as well as neural differentiation factors NR2F1, NR2F2, and p27Kip1. Knockdowns ofNOTCH1, SOX10, and their common effectorFABP7had negative effects on each other, inhibited spheroidogenesis, and induced cell death pointing at their essential roles in CSC maintenance. Downstream effects ofFABP7knockdown included suppression of a broad spectrum of genes involved in proliferation, ribosome biogenesis, and metabolism. Among proliferation-linked NOTCH1/FABP7 targets, we identified SKP2 and its substrate p27Kip1. A γ-secretase inhibitor, DAPT, selectively depleted CD133(+)cells, suppressed N1ICD and SKP2, induced p27Kip1, inhibited ACC growthin vivo, and sensitized CD133(+)cells to radiation.
CONCLUSIONS: These results establish in the majority of ACC the presence of a previously uncharacterized population of CD133(+)cells with neural stem properties, which are driven by SOX10, NOTCH1, and FABP7. Sensitivity of these cells to Notch inhibition and their dependence on SKP2 offer new opportunities for targeted ACC therapies.

Yasumoto Y, Miyazaki H, Vaidyan LK, et al.
Inhibition of Fatty Acid Synthase Decreases Expression of Stemness Markers in Glioma Stem Cells.
PLoS One. 2016; 11(1):e0147717 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Cellular metabolic changes, especially to lipid metabolism, have recently been recognized as a hallmark of various cancer cells. However, little is known about the significance of cellular lipid metabolism in the regulation of biological activity of glioma stem cells (GSCs). In this study, we examined the expression and role of fatty acid synthase (FASN), a key lipogenic enzyme, in GSCs. In the de novo lipid synthesis assay, GSCs exhibited higher lipogenesis than differentiated non-GSCs. Western blot and immunocytochemical analyses revealed that FASN is strongly expressed in multiple lines of patient-derived GSCs (G144 and Y10), but its expression was markedly reduced upon differentiation. When GSCs were treated with 20 μM cerulenin, a pharmacological inhibitor of FASN, their proliferation and migration were significantly suppressed and de novo lipogenesis decreased. Furthermore, following cerulenin treatment, expression of the GSC markers nestin, Sox2 and fatty acid binding protein (FABP7), markers of GCSs, decreased while that of glial fibrillary acidic protein (GFAP) expression increased. Taken together, our results indicate that FASN plays a pivotal role in the maintenance of GSC stemness, and FASN-mediated de novo lipid biosynthesis is closely associated with tumor growth and invasion in glioblastoma.

Li H, Zhao X, Yan X, et al.
Runx1 contributes to neurofibromatosis type 1 neurofibroma formation.
Oncogene. 2016; 35(11):1468-74 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Neurofibromatosis type 1 (NF1) patients are predisposed to neurofibromas but the driver(s) that contribute to neurofibroma formation are not fully understood. By cross comparison of microarray gene lists on human neurofibroma-initiating cells and developed neurofibroma Schwann cells (SCs) we identified RUNX1 overexpression in human neurofibroma initiation cells, suggesting RUNX1 might relate to neurofibroma formation. Immunostaining confirmed RUNX1 protein overexpression in human plexiform neurofibromas. Runx1 overexpression was confirmed in mouse Schwann cell progenitors (SCPs) and mouse neurofibromas at the messenger RNA and protein levels. Genetic inhibition of Runx1 expression by small hairpin RNA or pharmacological inhibition of Runx1 function by a Runx1/Cbfβ interaction inhibitor, Ro5-3335, decreased mouse neurofibroma sphere number in vitro. Targeted genetic deletion of Runx1 in SCs and SCPs delayed mouse neurofibroma formation in vivo. Mechanistically, loss of Nf1 increased embryonic day 12.5 Runx1(+)/Blbp(+) progenitors that enable tumor formation. These results suggest that Runx1 has an important role in Nf1 neurofibroma initiation, and inhibition of RUNX1 function might provide a novel potential therapeutic treatment strategy for neurofibroma patients.

Zhou J, Yong WP, Yap CS, et al.
An integrative approach identified genes associated with drug response in gastric cancer.
Carcinogenesis. 2015; 36(4):441-51 [PubMed] Related Publications
Gastric cancer (GC) is the second leading cause of global cancer mortality worldwide. However, the molecular mechanism underlying its carcinogenesis and drug resistance is not well understood. To identify novel functionally important genes that were differentially expressed due to combinations of genetic and epigenetic changes, we analyzed datasets containing genome-wide mRNA expression, DNA copy number alterations and DNA methylation status from 154 primary GC samples and 47 matched non-neoplastic mucosa tissues from Asian patients. We used concepts of 'within' and 'between' statistical analysis to compare the difference between tumors and controls within each platform, and assessed the correlations between platforms. This 'multi-regulated gene (MRG)' analysis identified 126 differentially expressed genes that underwent a combination of copy number and DNA methylation changes. Most genes were located at genomic loci associated with GC. Statistical enrichment analysis showed that MRGs were enriched for cancer, GC and drug response. We analysed several MRGs that previously had not been associated with GC. Knockdown of DDX27, TH1L or IDH3G sensitized cells to epirubicin or cisplatin, and knockdown of RAI14 reduced cell proliferation. Further studies showed that overexpression of DDX27 reduced epirubicin-induced DNA damage and apoptosis. Levels of DDX27 mRNA and protein were increased in early-stage gastric tumors, and may be a potential diagnostic and prognostic marker for GC. In summary, we used an integrative bioinformatics strategy to identify novel genes that are altered in GC and regulate resistance of GC cells to drugs in vitro.

Wee S, Niklasson M, Marinescu VD, et al.
Selective calcium sensitivity in immature glioma cancer stem cells.
PLoS One. 2014; 9(12):e115698 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Tumor-initiating cells are a subpopulation in aggressive cancers that exhibit traits shared with stem cells, including the ability to self-renew and differentiate, commonly referred to as stemness. In addition, such cells are resistant to chemo- and radiation therapy posing a therapeutic challenge. To uncover stemness-associated functions in glioma-initiating cells (GICs), transcriptome profiles were compared to neural stem cells (NSCs) and gene ontology analysis identified an enrichment of Ca2+ signaling genes in NSCs and the more stem-like (NSC-proximal) GICs. Functional analysis in a set of different GIC lines regarding sensitivity to disturbed homeostasis using A23187 and Thapsigargin, revealed that NSC-proximal GICs were more sensitive, corroborating the transcriptome data. Furthermore, Ca2+ drug sensitivity was reduced in GICs after differentiation, with most potent effect in the NSC-proximal GIC, supporting a stemness-associated Ca2+ sensitivity. NSCs and the NSC-proximal GIC line expressed a larger number of ion channels permeable to potassium, sodium and Ca2+. Conversely, a higher number of and higher expression levels of Ca2+ binding genes that may buffer Ca2+, were expressed in NSC-distal GICs. In particular, expression of the AMPA glutamate receptor subunit GRIA1, was found to associate with Ca2+ sensitive NSC-proximal GICs, and decreased as GICs differentiated along with reduced Ca2+ drug sensitivity. The correlation between high expression of Ca2+ channels (such as GRIA1) and sensitivity to Ca2+ drugs was confirmed in an additional nine novel GIC lines. Calcium drug sensitivity also correlated with expression of the NSC markers nestin (NES) and FABP7 (BLBP, brain lipid-binding protein) in this extended analysis. In summary, NSC-associated NES+/FABP7+/GRIA1+ GICs were selectively sensitive to disturbances in Ca2+ homeostasis, providing a potential target mechanism for eradication of an immature population of malignant cells.

Steiner J, Davis J, McClellan J, et al.
Dose-dependent benefits of quercetin on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer.
Cancer Biol Ther. 2014; 15(11):1456-67 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Breast cancer is the leading cause of cancer related death in women. Quercetin is a flavonol shown to have anti-carcinogenic actions. However, few studies have investigated the dose-dependent effects of quercetin on tumorigenesis and none have used the C3(1)/SV40 Tag breast cancer mouse model. At 4 weeks of age female C3(1)/SV40 Tag mice were randomized to one of four dietary treatments (n = 15-16/group): control (no quercetin), low-dose quercetin (0.02% diet), moderate-dose quercetin (0.2% diet), or high-dose quercetin (2% diet). Tumor number and volume was assessed twice a week and at sacrifice (20 wks). Results showed an inverted 'U' dose-dependent effect of dietary quercetin on tumor number and volume; at sacrifice the moderate dose was most efficacious and reduced tumor number 20% and tumor volume 78% compared to control mice (C3-Con: 9.0 ± 0.9; C3-0.2%: 7.3 ± 0.9) and (C3-Con: 2061.8 ± 977.0 mm(3); and C3-0.2%: 462.9 ± 75.9 mm(3)). Tumor volume at sacrifice was also reduced by the moderate dose compared to the high and low doses (C3-2%: 1163.2 ± 305.9 mm(3); C3-0.02%: 1401.5 ± 555.6 mm(3)), as was tumor number (C3-2%: 10.7 ± 1.3 mm(3); C3-0.02%: 8.1 ± 1.1 mm(3)). Gene expression microarray analysis performed on mammary glands from C3-Con and C3-0.2% mice determined that 31 genes were down-regulated and 9 genes were up-regulated more than 2-fold (P < 0.05) by quercetin treatment. We report the novel finding that there is a distinct dose-dependent effect of quercetin on tumor number and volume in a transgenic mouse model of human breast cancer, which is associated with a specific gene expression signature related to quercetin treatment.

Gromov P, Espinoza JA, Talman ML, et al.
FABP7 and HMGCS2 are novel protein markers for apocrine differentiation categorizing apocrine carcinoma of the breast.
PLoS One. 2014; 9(11):e112024 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Apocrine carcinoma of the breast is a distinctive malignancy with unique morphological and molecular features, generally characterized by being negative for estrogen and progesterone receptors, and thus not electable for endocrine therapy. Despite the fact that they are morphologically distinct from other breast lesions, no standard molecular criteria are currently available for their diagnosis. Using gel-based proteomics in combination with mass spectrometry and immunohistochemistry we have identified two novel markers, HMGCS2 and FABP7 that categorize the entire breast apocrine differentiation spectrum from benign metaplasia and cysts to invasive stages. Expression of HMGCS2 and FABP7 is strongly associated with apocrine differentiation; their expression is retained by most invasive apocrine carcinomas (IAC) showing positive immunoreactivity in 100% and 78% of apocrine carcinomas, respectively, as compared to non-apocrine tumors (16.7% and 6.8%). The nuclear localization of FABP7 in tumor cells was shown to be associated with more aggressive stages of apocrine carcinomas. In addition, when added to the panel of apocrine biomarkers previously reported by our group: 15-PGDH, HMGCR and ACSM1, together they provide a signature that may represent a golden molecular standard for defining the apocrine phenotype in the breast. Moreover, we show that combining HMGCS2 to the steroidal profile (HMGCS2+/Androgen Receptor (AR)+/Estrogen Receptor(ER)-/Progesteron Receptor (PR)- identifies IACs with a greater sensitivity (79%) as compared with the steroidal profile (AR+/ER-/PR-) alone (54%). We have also presented a detailed immunohistochemical analysis of breast apocrine lesions with a panel of antibodies against proteins which correspond to 10 genes selected from published transcriptomic signatures that currently characterize molecular apocrine subtype and shown that except for melanophilin that is overexpressed in benign apocrine lesions, these proteins were not specific for morphological apocrine differentiation in breast.

Bensaad K, Favaro E, Lewis CA, et al.
Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation.
Cell Rep. 2014; 9(1):349-65 [PubMed] Related Publications
An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via β-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo.

Zhou J, Deng Z, Chen Y, et al.
Overexpression of FABP7 promotes cell growth and predicts poor prognosis of clear cell renal cell carcinoma.
Urol Oncol. 2015; 33(3):113.e9-17 [PubMed] Related Publications
OBJECTIVES: Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies; however, the molecular events supporting RCC carcinogenesis remain poorly understood. The aim of the present study was to determine the differential expression of genes between normal kidney and clear cell RCC (ccRCC) samples and investigate the biological function of the most frequently altered gene in RCC cells.
MATERIALS AND METHODS: The gene expression profiles of 60 ccRCC and matched normal kidney samples from The Cancer Genome Atlas were analyzed. The altered genes were subjected to functional annotation clustering and integrative pathway analysis. The expression of one of the most frequently altered gene, fatty acid-binding protein (FABP) 7, in ccRCC and matched normal kidney samples was verified by immunohistochemistry and the association between FABP7 level and patient survival was investigated. Furthermore, FABP7 DNA copy number alteration, methylation, and mutation status in ccRCC from The Cancer Genome Atlas were analyzed. Finally, FABP7-overexpressing RCC cells were generated to determine the function of FABP7 in cell growth and the potential mechanisms of action.
RESULTS: FABP7 was significantly up-regulated in ccRCC, and the expression of FABP7 positively correlated with advanced clinical stage and poor survival of patients with ccRCC. FABP7 DNA copy number alteration was not frequently detected in ccRCC, and no mutation of FABP7 was found. FABP7 messenger RNA expression inversely correlated with its DNA methylation. Overexpression of FABP7 in RCC cells enhanced cell growth, clonogenicity, cell cycle progression and activated both extracellular-signal-regulated kinases (ERK) and signal transducer and activator of transcription 3 (Stat3) signaling.
CONCLUSION: FABP7 is overexpressed in ccRCC and promotes cell growth by the activation of ERK and Stat3 signaling pathways. Evidence from the clinical observations and experimental data suggests that FABP7 is a novel prognostic marker and potential therapeutic target for ccRCC.

Lock FE, Rebollo R, Miceli-Royer K, et al.
Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma.
Proc Natl Acad Sci U S A. 2014; 111(34):E3534-43 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences harbor multiple regulatory motifs and hence are capable of influencing expression of host genes. In response to environmental changes, TEs are known to be released from epigenetic repression and to become transcriptionally active. Such activation could also lead to lineage-inappropriate activation of oncogenes, as one study described in Hodgkin lymphoma. However, little further evidence for this mechanism in other cancers has been reported. Here, we reanalyzed whole transcriptome data from a large cohort of patients with diffuse large B-cell lymphoma (DLBCL) compared with normal B-cell centroblasts to detect genes ectopically expressed through activation of TE promoters. We have identified 98 such TE-gene chimeric transcripts that were exclusively expressed in primary DLBCL cases and confirmed several in DLBCL-derived cell lines. We further characterized a TE-gene chimeric transcript involving a fatty acid-binding protein gene (LTR2-FABP7), normally expressed in brain, that was ectopically expressed in a subset of DLBCL patients through the use of an endogenous retroviral LTR promoter of the LTR2 family. The LTR2-FABP7 chimeric transcript encodes a novel chimeric isoform of the protein with characteristics distinct from native FABP7. In vitro studies reveal a dependency for DLBCL cell line proliferation and growth on LTR2-FABP7 chimeric protein expression. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in cancer and suggest that LTR2-FABP7 may contribute to the pathogenesis of DLBCL in a subgroup of patients.

Schnell A, Chappuis S, Schmutz I, et al.
The nuclear receptor REV-ERBα regulates Fabp7 and modulates adult hippocampal neurogenesis.
PLoS One. 2014; 9(6):e99883 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
The function of the nuclear receptor Rev-erbα (Nr1d1) in the brain is, apart from its role in the circadian clock mechanism, unknown. Therefore, we compared gene expression profiles in the brain between wild-type and Rev-erbα knock-out (KO) animals. We identified fatty acid binding protein 7 (Fabp7, Blbp) as a direct target of repression by REV-ERBα. Loss of Rev-erbα manifested in memory and mood related behavioral phenotypes and led to overexpression of Fabp7 in various brain areas including the subgranular zone (SGZ) of the hippocampus, where neuronal progenitor cells (NPCs) can initiate adult neurogenesis. We found increased proliferation of hippocampal neurons and loss of its diurnal pattern in Rev-erbα KO mice. In vitro, proliferation and migration of glioblastoma cells were affected by manipulating either Fabp7 expression or REV-ERBα activity. These results suggest an important role of Rev-erbα and Fabp7 in adult neurogenesis, which may open new avenues for treatment of gliomas as well as neurological diseases such as depression and Alzheimer.

Pöschl J, Stark S, Neumann P, et al.
Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts.
Acta Neuropathol. 2014; 128(1):123-36 [PubMed] Related Publications
Medulloblastoma is a malignant embryonal brain tumor with highly variable outcome. In order to study the biology of this tumor and to perform preclinical treatment studies, a lot of effort has been put into the generation of appropriate mouse models. The usage of these models, however, has become debatable with the advances in human medulloblastoma subgrouping. This study brings together multiple relevant mouse models and matches genetic alterations and gene expression data of 140 murine tumors with 423 human medulloblastomas in a global way. Using AGDEX analysis and k-means clustering, we show that the Blbp-cre::Ctnnb1(ex3)(Fl/+)Trp53 (Fl/Fl) mouse model fits well to human WNT medulloblastoma, and that, among various Myc- or Mycn-based mouse medulloblastomas, tumors in Glt1-tTA::TRE-MYCN/Luc mice proved to be most specific for human group 3 medulloblastoma. None of the analyzed models displayed a significant match to group 4 tumors. Intriguingly, mice with Ptch1 or Smo mutations selectively modeled SHH medulloblastomas of adulthood, although such mutations occur in all human age groups. We therefore suggest that the infantile or adult gene expression pattern of SHH MBs are not solely determined by specific mutations. This is supported by the observation that human medulloblastomas with PTCH1 mutations displayed more similarities to PTCH1 wild-type tumors of the same age group than to PTCH1-mutated tumors of the other age group. Together, we provide novel insights into previously unrecognized specificity of distinct models and suggest these findings as a solid basis to choose the appropriate model for preclinical studies on medulloblastoma.

Feng JY, Diao XW, Fan MQ, et al.
Screening of feature genes of the renal cell carcinoma with DNA microarray.
Eur Rev Med Pharmacol Sci. 2013; 17(22):2994-3001 [PubMed] Related Publications
AIM: To investigate the underlying molecular mechanisms of renal cell carcinoma (RCC) by using the microarray expression profiles of normal kidney and RCC tissue for early diagnosis and treatment of RCC.
MATERIALS AND METHODS: The gene expression profile of GES781 was downloaded from Gene Expression Omnibus database, including including nine tissue samples of RCC tissues removed from nine patients and eight adjacent normal renal tissue samples. We identified the differentially expressed genes (DEGs) by Multtest package in R software. The screened DEGs were further analyzed by bioinformatics methods. Firstly, the comparison of the DEGs expression degree was performed by cluster analysis. Secondly, DAVID was used to perform functional analysis of up- and down- regulated genes and the protein-protein interaction (PPI) networks were constructed by prePPI. Finally, the pathways of genes in PPI networks were discovered by WebGestalt.
RESULTS: Compared with the control, we screened 648 down-regulated and 681 up-regulated DEGs. And the down- and up-regulated DEGs with maximum expression degree were UMOD (uromodulin) and FABP7 (fatty acid binding protein 7), respectively. There was significant difference in the gene expression between the normal kidney and RCC tissue. The up-regulated DEGs in RCC tissue were significantly related to the immune responses and the down-regulated DEGs were significantly related to the oxidation reduction. The most significant pathway in the PPI network of UMOD was cytokine-cytokine receptor interaction.
CONCLUSIONS: The screened DEGs have the potential to become candidate target molecules to monitor, diagnose and treat the RCC, and might be beneficial for the early diagnosis and medication control of RCC.

Morihiro Y, Yasumoto Y, Vaidyan LK, et al.
Fatty acid binding protein 7 as a marker of glioma stem cells.
Pathol Int. 2013; 63(11):546-53 [PubMed] Related Publications
Glioblastomas are the most aggressive brain tumors. Glioblastoma stem cells (GSCs) are thought to be responsible for the recurrence, chemoresistance, and poor prognosis of glioblastoma. Fatty acid binding protein 7 (FABP7), which is a cellular chaperone for a variety of omega-3 fatty acids, is a known marker for neural stem cells. In this study, using a newly developed anti-FABP7 antibody and patient-derived GSC lines, we evaluated the expression of FABP7 in GSCs. Using immunocytochemistry, Western blotting, and qPCR analyses, FABP7 was found to be highly enriched in GSCs and its localization was found in cytosol and nuclei. FABP7 expression was significantly downregulated in differentiated GSCs induced by the addition of serum. In the glioma surgical specimens, FABP7 was highly expressed in the majority of glioblastoma. Double immunostaining for FABP7 and Sox2 showed that FABP7(+) Sox2(+) tumor cells were significantly increased in glioblastoma (grade IV) compared with diffuse astrocytoma (grade II) and anaplastic astrocytoma (grade III). Our data introduces FABP7 as a marker for GSCs and further highlights its possible significance for glioma diagnosis and treatment.

Grupenmacher AT, Halpern AL, Bonaldo Mde F, et al.
Study of the gene expression and microRNA expression profiles of malignant rhabdoid tumors originated in the brain (AT/RT) and in the kidney (RTK).
Childs Nerv Syst. 2013; 29(11):1977-83 [PubMed] Related Publications
PURPOSE: Malignant rhabdoid tumors (MRT) can occur in a variety of anatomical sites. The most frequent locations are the brain, where they are named atypical teratoid/rhabdoid tumors (AT/RT), and the kidney, where they are named rhabdoid tumors of the kidney (RTK). MRTs at all sites are recognized as the same entity due to their similar morphology, aggressive behavior, and a common genetic abnormality, an inactivating mutation of the SMARCB1/INI-1/hSNF5/BAF47 gene. We aim to investigate potential molecular differences between AT/RT and RTK.
METHODS: We analyzed the microRNA (miRNA) and gene expression (GE) profiles of 10 RTK, 13 AT/RT, and 2 human MRT cell lines (G401-RTK and MON-AT/RT). Illumina V2 MicroRNA Chips (Illumina, Inc., CA, USA) were used for miRNA analysis, and Illumina HT-12 whole genome expression arrays were used for GE analysis.
RESULTS: The distribution of p values from GE showed a significant difference between RTK and AT/RT, with 20 % of the genes having p values ≤0.05 and the principal component analysis of the GE data showed separation between RTK and AT/RT. However, the miRNA expression failed to identify the different tumor groups. Among the 122 genes significantly differentially expressed between AT/RT and RTK, we found both genes related to brain development (i.e., FABP7, 22-fold increase in AT/RT) and genes related to kidney development (i.e., TCF21, sixfold increase in RTK).
CONCLUSION: Based on our results, we hypothesized that although MRT are indeed the same tumor, independent of the site of origin, the GE differences reflect the influence of microenvironment over tumor development.

Kaul A, Chen YH, Emnett RJ, et al.
Conditional KIAA1549:BRAF mice reveal brain region- and cell type-specific effects.
Genesis. 2013; 51(10):708-16 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Low-grade brain tumors (pilocytic astrocytomas) that result from a genomic rearrangement in which the BRAF kinase domain is fused to the amino terminal of the KIAA1549 gene (KIAA1549:BRAF fusion; f-BRAF) commonly arise in the cerebellum of young children. To model this temporal and spatial specificity in mice, we generated conditional KIAA1549:BRAF strains that coexpresses green fluorescent protein (GFP). Although both primary astrocytes and neural stem cells (NSCs) from these mice express f-BRAF and GFP as well as exhibit increased MEK activity, only f-BRAF-expressing NSCs exhibit increased proliferation in vitro. Using Cre driver lines in which KIAA1549:BRAF expression was directed to NSCs (f-BRAF; BLBP-Cre mice), astrocytes (f-BRAF; GFAP-Cre mice), and NG2 progenitor cells (f-BRAF; NG2-Cre mice), increased glial cell numbers were observed only in the cerebellum of f-BRAF; BLBP-Cre mice in vivo. The availability of this unique KIAA1549:BRAF conditional transgenic mouse strain will enable future mechanistic studies aimed at defining the developmentally-regulated temporal and spatial determinants that underlie low-grade astrocytoma formation in children.

Brun M, Glubrecht DD, Baksh S, Godbout R
Calcineurin regulates nuclear factor I dephosphorylation and activity in malignant glioma cell lines.
J Biol Chem. 2013; 288(33):24104-15 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Malignant gliomas (MG), including grades III and IV astrocytomas, are the most common adult brain tumors. These tumors are highly aggressive with a median survival of less than 2 years. Nuclear factor I (NFI) is a family of transcription factors that regulates the expression of glial genes in the developing brain. We have previously shown that regulation of the brain fatty acid-binding protein (B-FABP; FABP7) and glial fibrillary acidic protein (GFAP) genes in MG cells is dependent on the phosphorylation state of NFI, with hypophosphorylation of NFI correlating with GFAP and B-FABP expression. Importantly, NFI phosphorylation is dependent on phosphatase activity that is enriched in GFAP/B-FABP+ve cells. Using chromatin immunoprecipitation, we show that NFI occupies the GFAP and B-FABP promoters in NFI-hypophosphorylated GFAP/B-FABP+ve MG cells. NFI occupancy, NFI-dependent transcriptional activity, and NFI phosphorylation are all modulated by the serine/threonine phosphatase calcineurin. Importantly, a cleaved form of calcineurin, associated with increased phosphatase activity, is specifically expressed in NFI-hypophosphorylated GFAP/B-FABP+ve MG cells. Calcineurin in GFAP/B-FABP+ve MG cells localizes to the nucleus. In contrast, calcineurin is primarily found in the cytoplasm of GFAP/B-FABP-ve cells, suggesting a dual mechanism for calcineurin activation in MG. Finally, our results demonstrate that calcineurin expression is up-regulated in areas of high infiltration/migration in grade IV astrocytoma tumor tissue. Our data suggest a critical role for calcineurin in NFI transcriptional regulation and in the determination of MG infiltrative properties.

De Rosa A, Pellegatta S, Rossi M, et al.
A radial glia gene marker, fatty acid binding protein 7 (FABP7), is involved in proliferation and invasion of glioblastoma cells.
PLoS One. 2012; 7(12):e52113 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Glioblastoma multiforme (GBM) is among the most deadly cancers. A number of studies suggest that a fraction of tumor cells with stem cell features (Glioma Stem-like Cells, GSC) might be responsible for GBM recurrence and aggressiveness. GSC similarly to normal neural stem cells, can form neurospheres (NS) in vitro, and seem to mirror the genetic features of the original tumor better than glioma cells growing adherently in the presence of serum. Using cDNA microarray analysis we identified a number of relevant genes for glioma biology that are differentially expressed in adherent cells and neurospheres derived from the same tumor. Fatty acid-binding protein 7 (FABP7) was identified as one of the most highly expressed genes in NS compared to their adherent counterpart. We found that down-regulation of FABP7 expression in NS by small interfering RNAs significantly reduced cell proliferation and migration. We also evaluated the potential involvement of FABP7 in response to radiotherapy, as this treatment may cause increased tumor infiltration. Migration of irradiated NS was associated to increased expression of FABP7. In agreement with this, in vivo reduced tumorigenicity of GBM cells with down-regulated expression of FABP7 was associated to decreased expression of the migration marker doublecortin. Notably, we observed that PPAR antagonists affect FABP7 expression and decrease the migration capability of NS after irradiation. As a whole, the data emphasize the role of FABP7 expression in GBM migration and provide translational hints on the timing of treatment with anti-FABP7 agents like PPAR antagonists during GBM evolution.

Liu RZ, Monckton EA, Godbout R
Regulation of the FABP7 gene by PAX6 in malignant glioma cells.
Biochem Biophys Res Commun. 2012; 422(3):482-7 [PubMed] Related Publications
Brain fatty acid-binding protein (FABP7) and PAX6 are both expressed in radial glial cells and have been implicated in neurogenesis and glial cell differentiation. FABP7 and PAX6 have also been postulated to play a role in malignant glioma cell growth and invasion. Here, we address the role of PAX6 in regulating FABP7 gene expression in malignant glioma cells. We report that PAX6 and FABP7 RNA are generally co-expressed in malignant glioma cell lines, tumors and tumor neurospheres. Using the CAT reporter gene assay, we show that FABP7 promoter activity is upregulated by PAX6. Sequential deletion analysis of the FABP7 promoter, combined with gel shift and supershift assays demonstrate the presence of a PAX6 responsive region located upstream of the FABP7 gene, at -862 to -1033 bp. Inclusion of sequences between -1.2 and -1.8 kb reduced CAT activity, suggesting the presence of a repressor element within this region. While PAX6 overexpression did not induce endogenous FABP7 expression in FABP7-negative cells, knock-down of PAX6 in PAX6-positive malignant glioma cells resulted in reduced FABP7 levels. These data provide the first evidence of direct transactivation of the FABP7 proximal promoter by PAX6 and suggest a synergistic mechanism for PAX6 and other co-factor(s) in regulating FABP7 expression in malignant glioma.

Alshareeda AT, Rakha EA, Nolan CC, et al.
Fatty acid binding protein 7 expression and its sub-cellular localization in breast cancer.
Breast Cancer Res Treat. 2012; 134(2):519-29 [PubMed] Related Publications
FABP7 is a member of the multi-gene fatty acid binding protein family. It is expressed in the mammary gland and has been shown to function as inhibitor of proliferation of breast tumour cells and to promote differentiation through the JAK/Stat pathway. Cytoplasmic FABP7 expression has been shown to be associated with a favourable prognosis of basal-like breast cancer. In other tissues, varying sub-cellular localization of FABP7 between the nucleus and cytoplasm has been observed. Tissue microarray preparations of well-characterized series of 1,249 unselected and 245 ER-negative invasive breast cancers with a long-term follow-up were investigated in this study to assess the biological and clinical significance of FABP7 sub-cellular localization using immunohistochemistry. Both nuclear and cytoplasmic FABP7 were observed. Nuclear FABP7 was associated with high histologic grade, mitotic frequency, pleomorphism and stage, in addition to basal phenotype (BP) and triple-negative (TN) phenotype. Nuclear FABP7 expression showed an association with expression of markers associated with proliferation and cell-cycle control including Ki67, p53 and p21; however, cytoplasmic FABP7 was associated only with Ki67 and P53 (P = 0.001, < 0.001 respectively). Interestingly, in multivariate analysis, nuclear FABP7 expression in BP was significantly associated with longer DFI (P = 0.025) independent of cytoplasmic expression. Tumours with only nuclear positive FABP7 expression had significantly better prognosis than those with only cytoplasmic expression. This is the first study elucidating the sub-cellular localization of FABP7 in a large series of breast cancer cases. Our observations demonstrate the considerable heterogeneity in expression patterns of FABP7 within breast cancer that relates to differences in biological behaviour especially in basal-like breast cancer. Further investigation of the biology of FABP7 in breast cancer is warranted.

Slipicevic A, Holm R, Emilsen E, et al.
Cytoplasmic BRMS1 expression in malignant melanoma is associated with increased disease-free survival.
BMC Cancer. 2012; 12:73 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
BACKGROUND/AIMS: Breast cancer metastasis suppressor 1 (BRMS1) blocks metastasis in melanoma xenografts; however, its usefulness as a biomarker in human melanomas has not been widely studied. The goal was to measure BRMS1 expression in benign nevi, primary and metastatic melanomas and evaluate its impact on disease progression and prognosis.
METHODS: Paraffin-embedded tissue from 155 primary melanomas, 69 metastases and 15 nevi was examined for BRMS1 expression using immunohistochemistry. siRNA mediated BRMS1 down-regulation was used to study impact on invasion and migration in melanoma cell lines.
RESULTS: A significantly higher percentage of nevi (87%), compared to primary melanomas (20%) and metastases (48%), expressed BRMS1 in the nucelus (p < 0.0001). Strong nuclear staining intensity was observed in 67% of nevi, and in 9% and 24% of the primary and metastatic melanomas, respectively (p < 0.0001). Comparable cytoplasmic expression was observed (nevi; 87%, primaries; 86%, metastases; 72%). However, a decline in cytoplasmic staining intensity was observed in metastases compared to nevi and primary tumors (26%, 47%, and 58%, respectively, p < 0.0001). Score index (percentage immunopositive celles multiplied with staining intensity) revealed that high cytoplasmic score index (≥ 4) was associated with thinner tumors (p = 0.04), lack of ulceration (p = 0.02) and increased disease-free survival (p = 0.036). When intensity and percentage BRMS1 positive cells were analyzed separately, intensity remained associated with tumor thickness (p = 0.024) and ulceration (p = 0.004) but was inversely associated with expression of proliferation markers (cyclin D3 (p = 0.008), cyclin A (p = 0.007), and p21Waf1/Cip1 (p = 0.009)). Cytoplasmic score index was inversely associated with nuclear p-Akt (p = 0.013) and positively associated with cytoplasmic p-ERK1/2 expression (p = 0.033). Nuclear BRMS1 expression in ≥ 10% of primary melanoma cells was associated with thicker tumors (p = 0.016) and decreased relapse-free period (p = 0.043). Nuclear BRMS1 was associated with expression of fatty acid binding protein 7 (FABP7; p = 0.011), a marker of invasion in melanomas. In line with this, repression of BRMS1 expression reduced the ability of melanoma cells to migrate and invade in vitro.
CONCLUSION: Our data suggest that BRMS1 is localized in cytoplasm and nucleus of melanocytic cells and that cellular localization determines its in vivo effect. We hypothesize that cytoplasmic BRMS1 restricts melanoma progression while nuclear BRMS1 possibly promotes melanoma cell invasion.Please see related article: http://www.biomedcentral.com/1741-7015/10/19.

Liu RZ, Graham K, Glubrecht DD, et al.
A fatty acid-binding protein 7/RXRβ pathway enhances survival and proliferation in triple-negative breast cancer.
J Pathol. 2012; 228(3):310-21 [PubMed] Related Publications
FABP7 has been implicated in tumour cell proliferation, cell migration, and poor prognosis in patients with high-grade astrocytoma and melanoma. In this study, we examine FABP7 expression in a cohort of 176 primary breast cancers by gene profiling and tissue microarray immunostaining. We show that FABP7 is significantly up-regulated in triple-negative breast cancer. Elevated FABP7 levels are associated with poor prognosis, absence of oestrogen and progesterone hormone receptors (ER, PR) and HER2, increased cell proliferation, and high tumour grade. Depletion of FABP7 in the ER/PR-negative cell line, MDA-MB-435S, significantly reduced cell growth rate and sensitized the cells to growth inhibition by omega-3 docosahexaenoic acid (DHA). A target of DHA-bound FABP7 in the nucleus is RXRβ, a retinoid-activated nuclear receptor that functions as a transcription factor by either homodimerizing or heterodimerizing with other nuclear receptors such as PPARs. Based on our microarray data, RXRβ, like FABP7, is an adverse prognostic factor for breast cancer. We propose that the DHA-FABP7-RXRβ pathway promotes cell survival/proliferation in triple-negative breast cancer. Targeting this pathway may thus provide an alternate route for the treatment of triple-negative breast cancer.

Raimondo F, Salemi C, Chinello C, et al.
Proteomic analysis in clear cell renal cell carcinoma: identification of differentially expressed protein by 2-D DIGE.
Mol Biosyst. 2012; 8(4):1040-51 [PubMed] Related Publications
Renal cell carcinoma (RCC), the most common neoplasm affecting the adult kidney, is characterised by heterogeneity of histological subtypes, drug resistance, and absence of molecular markers. Two-dimensional difference gel electrophoresis (2-D DIGE) technology in combination with mass spectrometry (MS) was applied to detect differentially expressed proteins in 20 pairs of RCC tissues and matched adjacent normal kidney cortex (ANK), in order to search for RCC markers. After gel analysis by DeCyder 6.5 and EDA software, differentially expressed protein spots were excised from Deep Purple stained preparative 2DE gel. A total of 100 proteins were identified by MS out of 2500 spots, 23 and 77 of these were, respectively, over- and down-expressed in RCC. The Principal Component Analysis applied to gels and protein spots exactly separated the two sample classes in two groups: RCC and ANK. Moreover, some spots, including ANXA2, PPIA, FABP7 and LEG1, resulted highly differential. The DIGE data were also confirmed by immunoblotting analysis for these proteins. In conclusion, we suggest that applying 2-D DIGE to RCC may provide the basis for a better molecular characterization and for the discovery of candidate biomarkers.

Qiang L, Wu T, Zhang HW, et al.
HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway.
Cell Death Differ. 2012; 19(2):284-94 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Hypoxia induces the expansion of glioblastoma stem cells (GSCs), but the mechanism underlying it is still unclear. Here, we supply evidence that hypoxia-inducible factor-1α (HIF-1α) induced activation of Notch pathway is essential for hypoxia-mediated maintenance of GSC. Either depletion of HIF-1α or inactivation of Notch signaling partly inhibits the hypoxia-mediated maintenance of GSC. Further data suggest a role for HIF-1α in the interaction and stabilization of intracellular domain of Notch (NICD), and activation of Notch signaling. The mRNA level of HIF-1α and Notch target gene FABP7 was elevated in GSC. And the STAT3 pathway responsible for the HIF-1α gene transcription, the phosphatidylinositol 3-kinase-Akt and ERK1/2, both of which are contributed to HIF-1α protein translation, are also preferentially activated in GSC. Inhibition of these pathways partly reduces the hypoxia-induced activation of the Notch pathway and subsequent GSC maintenance. Taken together, our findings suggest that HIF-1α requires Notch pathway to drive the maintenance of GSC. The activated regulation of HIF-1α makes GSC more sensitive to hypoxia-mediated maintenance. These findings enhance our understanding of mechanism of hypoxia-mediated GSC expansion and provide HIF-1α as an attractive target for glioblastoma therapy.

Takaoka N, Takayama T, Teratani T, et al.
Analysis of the regulation of fatty acid binding protein 7 expression in human renal carcinoma cell lines.
BMC Mol Biol. 2011; 12:31 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
BACKGROUND: Improving the treatment of renal cell carcinoma (RCC) will depend on the development of better biomarkers for predicting disease progression and aiding the design of appropriate therapies. One such marker may be fatty acid binding protein 7 (FABP7), also known as B-FABP and BLBP, which is expressed normally in radial glial cells of the developing central nervous system and cells of the mammary gland. Melanomas, glioblastomas, and several types of carcinomas, including RCC, overexpress FABP7. The abundant expression of FABP7 in primary RCCs compared to certain RCC-derived cell lines may allow the definition of the molecular components of FABP7's regulatory system.
RESULTS: We determined FABP7 mRNA levels in six RCC cell lines. Two were highly expressed, whereas the other and the embryonic kidney cell line (HEK293) were weakly expressed FABP7 transcripts. Western blot analysis of the cell lines detected strong FABP7 expression only in one RCC cell line. Promoter activity in the RCC cell lines was 3- to 21-fold higher than that of HEK293. Deletion analysis demonstrated that three FABP7 promoter regions contributed to upregulated expression in RCC cell lines, but not in the HEK293 cell. Competition analysis of gel shifts indicated that OCT1, OCT6, and nuclear factor I (NFI) bound to the FABP7 promoter region. Supershift experiments indicated that BRN2 (POU3F2) and NFI bound to the FABP7 promoter region as well. There was an inverse correlation between FABP7 promoter activity and BRN2 mRNA expression. The FABP7-positive cell line's NFI-DNA complex migrated faster than in other cell lines. Levels of NFIA mRNA were higher in the HEK293 cell line than in any of the six RCC cell lines. In contrast, NFIC mRNA expression was lower in the HEK293 cell line than in the six RCC cell lines.
CONCLUSIONS: Three putative FABP7 promoter regions drive reporter gene expression in RCC cell lines, but not in the HEK293 cell line. BRN2 and NFI may be key factors regulating the expression of FABP7 in certain RCC-derived cell lines.

Tölle A, Suhail S, Jung M, et al.
Fatty acid binding proteins (FABPs) in prostate, bladder and kidney cancer cell lines and the use of IL-FABP as survival predictor in patients with renal cell carcinoma.
BMC Cancer. 2011; 11:302 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
BACKGROUND: Fatty acid binding proteins (FABP) play an important role in carcinogenesis. Modified FABP expression patterns were described for prostate, bladder and for renal cell carcinoma. Studies on metabolic relationships and interactions in permanent cell lines allow a deeper insight into molecular processes. The aim of this study is therefore a systematic overview on mRNA and protein expressions of seven FABPs in frequently used urological cell lines.
METHODS: Nine cell lines of renal carcinomas, seven of urinary bladder carcinomas, and five of prostate carcinomas were investigated. Quantitative RT-qPCR and western blotting were used to determine different FABPs. In addition, 46 paired cancerous and noncancerous tissue samples from nephrectomy specimen with renal cell carcinomas were investigated regarding the ileum FABP mRNA expression level and associated with survival outcome.
RESULTS: General characteristics of all urological carcinoma cell lines were the expression of E-and IL-FABP on mRNA and protein level, while the expressions differed between the cell lines. The protein expression was not always congruent with the mRNA expression. Renal cell carcinoma cell lines showed expressions of L-, H- and B-FABP mRNA in addition to the general FABP expression in five out of the eight investigated cell lines. In bladder cancer cell lines, we additionally found the expression of A-FABP mRNA in six cell lines, while H-FABP was present only in three cell lines. In prostate cancer cell lines, a strong reduction of A- and E- FABP mRNA was observed. The expression of B-FABP mRNA and protein was observed only in the 22 RV-1 cells. IL-FABP mRNA was over-expressed in renal tumour tissue. The IL-FABP ratio was identified as an independent indicator of survival outcome.
CONCLUSIONS: Distinctly different FABP expression patterns were observed not only between the cell lines derived from the three cancer types, but also between the cell lines from the same cancer. The FABP patterns in the cell lines do not always reflect the real situation in the tumours. These facts have to be considered in functional studies concerning the different FABPs.

Yamaguchi K, Sakai M, Kim J, et al.
MRG-binding protein contributes to colorectal cancer development.
Cancer Sci. 2011; 102(8):1486-92 [PubMed] Related Publications
MRGBP (MORF4-related gene-binding protein; also known as chromosome 20 open reading frame 20) encodes a subunit of the transformation/transcription domain-associated protein (TRRAP)/tat-interacting protein 60 (TIP60)-containing histone acetyltransferase complex. We previously showed that MRGBP was upregulated in the majority of colorectal tumors, and the enhanced expression was associated with cell proliferation. In this study, we investigated its role in colorectal carcinogenesis and searched for genes regulated by MRGBP. Immunohistochemical staining of 22 adenomas and 47 carcinomas in the colon and rectum showed that high levels of MRGBP expression were observed more frequently in carcinomas (45%) than adenomas (5%), linking its role to malignant properties of colorectal tumors. No clinicopathological factors were associated with the levels MRGBP expression in colorectal cancer. Copy number analysis revealed that gene amplification is involved in the elevated expression. A genome-wide expression analysis identified a total of 41 genes upregulated by MRGBP. These genes were implicated in biological processes, including DNA replication, minichromosome maintenance, and cell division. Theses results suggest that MRGBP contributes to colorectal carcinogenesis through rendering advantages in cell proliferation and/or division of cancer cells. Our findings might be helpful for the identification of a specific biomarker for colorectal cancer and the development of diagnostic and/or therapeutic approaches.

Etcheverry A, Aubry M, de Tayrac M, et al.
DNA methylation in glioblastoma: impact on gene expression and clinical outcome.
BMC Genomics. 2010; 11:701 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
BACKGROUND: Changes in promoter DNA methylation pattern of genes involved in key biological pathways have been reported in glioblastoma. Genome-wide assessments of DNA methylation levels are now required to decipher the epigenetic events involved in the aggressive phenotype of glioblastoma, and to guide new treatment strategies.
RESULTS: We performed a whole-genome integrative analysis of methylation and gene expression profiles in 40 newly diagnosed glioblastoma patients. We also screened for associations between the level of methylation of CpG sites and overall survival in a cohort of 50 patients uniformly treated by surgery, radiotherapy and chemotherapy with concomitant and adjuvant temozolomide (STUPP protocol). The methylation analysis identified 616 CpG sites differentially methylated between glioblastoma and control brain, a quarter of which was differentially expressed in a concordant way. Thirteen of the genes with concordant CpG sites displayed an inverse correlation between promoter methylation and expression level in glioblastomas: B3GNT5, FABP7, ZNF217, BST2, OAS1, SLC13A5, GSTM5, ME1, UBXD3, TSPYL5, FAAH, C7orf13, and C3orf14. Survival analysis identified six CpG sites associated with overall survival. SOX10 promoter methylation status (two CpG sites) stratified patients similarly to MGMT status, but with a higher Area Under the Curve (0.78 vs. 0.71, p-value < 5e-04). The methylation status of the FNDC3B, TBX3, DGKI, and FSD1 promoters identified patients with MGMT-methylated tumors that did not respond to STUPP treatment (p-value < 1e-04).
CONCLUSIONS: This study provides the first genome-wide integrative analysis of DNA methylation and gene expression profiles obtained from the same GBM cohort. We also present a methylome-based survival analysis for one of the largest uniformly treated GBM cohort ever studied, for more than 27,000 CpG sites. We have identified genes whose expression may be tightly regulated by epigenetic mechanisms and markers that may guide treatment decisions.

Graham K, Ge X, de Las Morenas A, et al.
Gene expression profiles of estrogen receptor-positive and estrogen receptor-negative breast cancers are detectable in histologically normal breast epithelium.
Clin Cancer Res. 2011; 17(2):236-46 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
PURPOSE: Previously, we found that gene expression in histologically normal breast epithelium (NlEpi) from women at high breast cancer risk can resemble gene expression in NlEpi from cancer-containing breasts. Therefore, we hypothesized that gene expression characteristic of a cancer subtype might be seen in NlEpi of breasts containing that subtype.
EXPERIMENTAL DESIGN: We examined gene expression in 46 cases of microdissected NlEpi from untreated women undergoing breast cancer surgery. From 30 age-matched cases [15 estrogen receptor (ER)+, 15 ER-] we used Affymetryix U133A arrays. From 16 independent cases (9 ER+, 7 ER-), we validated selected genes using quantitative real-time PCR (qPCR). We then compared gene expression between NlEpi and invasive breast cancer using four publicly available data sets.
RESULTS: We identified 198 genes that are differentially expressed between NlEpi from breasts with ER+ (NlEpiER+) compared with ER- cancers (NlEpiER-). These include genes characteristic of ER+ and ER- cancers (e.g., ESR1, GATA3, and CX3CL1, FABP7). qPCR validated the microarray results in both the 30 original cases and the 16 independent cases. Gene expression in NlEpiER+ and NlEpiER- resembled gene expression in ER+ and ER- cancers, respectively: 25% to 53% of the genes or probes examined in four external data sets overlapped between NlEpi and the corresponding cancer subtype.
CONCLUSIONS: Gene expression differs in NlEpi of breasts containing ER+ compared with ER- breast cancers. These differences echo differences in ER+ and ER- invasive cancers. NlEpi gene expression may help elucidate subtype-specific risk signatures, identify early genomic events in cancer development, and locate targets for prevention and therapy.

Yamaguchi K, Sakai M, Shimokawa T, et al.
C20orf20 (MRG-binding protein) as a potential therapeutic target for colorectal cancer.
Br J Cancer. 2010; 102(2):325-31 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
BACKGROUND: Colorectal cancer is one of the most common causes of cancer death worldwide. Using cDNA microarray containing 23 040 genes, we earlier investigated gene-expression profiles in 11 colorectal cancers for the purpose of better understanding of colorectal carcinogenesis as well as development of novel diagnostic and therapeutic strategies. MRG-binding protein (MRGBP) or C20orf20, encoding a subunit of TRRAP/TIP60-containing histone acetyltransferase complex, was up-regulated in the majority of colorectal tumours.
METHODS AND RESULTS: The elevated expression of MRGBP was observed in colorectal cancer tissues by quantitative PCR as well as immunohistochemical analyses. MRGBP marginally expressed in normal vital organs. Notably, suppressed MRGBP expression by MRGBP short hairpin RNA inhibited proliferation of colorectal cancer cells. Yeast two-hybrid screening and subsequent immunoprecipitation analysis identified bromodomain containing 8 (BRD8) as an MRGBP-interacting protein. As RNA interference against BRD8 also suppressed proliferation of colorectal cancer cells, BRD8 may be an important down-stream target of MRGBP.
CONCLUSION: These results suggest that MRGBP has an important function in proliferation of cancer cells through the regulation of BRD8 and that MRGBP should be a novel therapeutic target for colorectal cancer.

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