Research IndicatorsGraph generated 11 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (2)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: CRABP1 (cancer-related)
Liu RZ, Li S, Garcia E, et al.Association between cytoplasmic CRABP2, altered retinoic acid signaling, and poor prognosis in glioblastoma.
Glia. 2016; 64(6):963-76 [PubMed
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Retinoic acid (RA), a metabolite of vitamin A, is required for the regulation of growth and development. Aberrant expression of molecules involved in RA signaling has been reported in various cancer types including glioblastoma multiforme (GBM). Cellular retinoic acid-binding protein 2 (CRABP2) has previously been shown to play a key role in the transport of RA to retinoic acid receptors (RARs) to activate their transcription regulatory activity. Here, we demonstrate that CRABP2 is predominantly located in the cytoplasm of GBM tumors. Cytoplasmic, but not nuclear, CRABP2 levels in GBM tumors are associated with poor patient survival. Treatment of malignant glioma cell lines with RA results in a dose-dependent increase in accumulation of CRABP2 in the cytoplasm. CRABP2 knockdown reduces proliferation rates of malignant glioma cells, and enhances RA-induced RAR activation. Levels of CRYAB, a small heat shock protein with anti-apoptotic activity, and GFAP, an astrocyte-specific intermediate filament protein, are greatly reduced in CRABP2-depleted cells. Restoration of CRYAB expression partially but significantly reversed the effect of CRABP2 depletion on RAR activation. Our combined in vivo and in vitro data indicate that: (i) CRABP2 is an important determinant of clinical outcome in GBM patients, and (ii) the mechanism of action of CRABP2 in GBM involves sequestration of RA in the cytoplasm and activation of an anti-apoptotic pathway, thereby enhancing proliferation and preventing RA-mediated cell death and differentiation. We propose that reducing CRABP2 levels may enhance the therapeutic index of RA in GBM patients.
Yang YP, Wang S, Li X, Schor NFCell Line-Dependent Variability of Coordinate Expression of p75NTR and CRABP1 and Modulation of Effects of Fenretinide on Neuroblastoma Cells.
Oxid Med Cell Longev. 2016; 2016:7568287 [PubMed
] Free Access to Full Article Related Publications
Neuroblastoma is a childhood neural crest tumor. Fenretinide, a retinoic acid analogue, induces accumulation of mitochondrial reactive oxygen species and consequent apoptosis in neuroblastoma cells. The p75 neurotrophin receptor (p75NTR) enhances the antineuroblastoma cell efficacy of fenretinide in vitro. We examined the role of the retinoid binding protein, CRABP1, in p75NTR-mediated potentiation of the efficacy of fenretinide. Knockdown and overexpression, respectively, of either p75NTR or CRABP1 were effected in neuroblastoma cell lines using standard techniques. Expression was determined by qRT-PCR and confirmed at the protein level by Western blot. Metabolic viability was determined by Alamar blue assay. While protein content of CRABP1 correlated roughly with that of p75NTR in the three neuroblastoid or epithelioid human neuroblastoma cell lines studied, manipulation of p75NTR expression resulted in cell line-dependent, variable change in CRABP1 expression. Furthermore, in some cell lines, induced expression of CRABP1 in the absence of p75NTR did not alter cell sensitivity to fenretinide treatment. The effects of manipulation of p75NTR expression on CRABP1 expression and the effects of CRABP1 expression on fenretinide efficacy are therefore neuroblastoma cell line-dependent. Potentiation of the antineuroblastoma cell effects of fenretinide by p75NTR is not mediated solely through CRABP1.
BACKGROUND: Clinical trials designed to test the efficacy of retinoic acid (RA) as an adjuvant for the treatment of solid cancers have been disappointing, primarily due to RA resistance. Estrogen receptor (ER)-negative breast cancer cells are more resistant to RA than ER-positive cells. The expression and subcellular distribution of two RA-binding proteins, FABP5 and CRABP2, has already been shown to play critical roles in breast cancer cell response to RA. CRABP1, a third member of the RA-binding protein family, has not previously been investigated as a possible mediator of RA action in breast cancer.
METHODS: CRABP1 and CRABP2 expression in primary breast tumor tissues was analyzed using gene expression and tissue microarrays. CRABP1 levels were manipulated using siRNAs and by transient overexpression. RA-induced subcellular translocation of CRABPs was examined by immunofluorescence microscopy and immunoblotting. RA-induced transactivation of RAR was analyzed using a RA response element (RARE)-driven luciferase reporter system. Effects of CRABP1 expression and RA treatment on downstream gene expression were investigated by semi-quantitative RT-PCR analysis.
RESULTS: Compared to normal mammary tissues, CRABP1 expression is significantly down-regulated in ER+ breast tumors, but maintained in triple-negative breast cancers. Elevated CRABP1 levels are associated with poor patient prognosis, high Ki67 immunoreactivity and high tumor grade in breast cancer. The prognostic significance of CRABP1 is attributed to its cytoplasmic localization. We demonstrate that CRABP1 expression attenuates RA-induced cell growth arrest and inhibits RA signalling in breast cancer cells by sequestering RA in the cytoplasm. We also show that CRABP1 affects the expression of genes involved in RA biosynthesis, trafficking and metabolism.
CONCLUSIONS: CRABP1 is an adverse factor for clinical outcome in triple-negative breast cancer and a potent inhibitor of RA signalling in breast cancer cells. Our data indicate that CRABP1, in conjunction with previously identified CRABP2 and FABP5, plays a key role in breast cancer cell response to RA. We propose that these three RA-binding proteins can serve as biomarkers for predicting triple-negative breast cancer response to RA, with elevated levels of either cytoplasmic CRABP1 or FABP5 associated with RA resistance, and elevated levels of nuclear CRABP2 associated with sensitivity to RA.
Capicua (CIC) has been implicated in pathogenesis of spinocerebellar ataxia type-1 (SCA1) neurodegenerative disease and some types of cancer; however, the role of CIC in prostate cancer remains unknown. Here we show that CIC suppresses prostate cancer progression. CIC expression was markedly decreased in human prostatic carcinoma. CIC overexpression suppressed prostate cancer cell proliferation, invasion, and migration, whereas CIC RNAi exerted opposite effects. We found that knock-down of CIC derepresses expression of ETV5 and CRABP1 in LNCaP and PC-3 cells, respectively, thereby promoting cell proliferation and invasion. We also discovered that miR-93, miR-106b, and miR-375, which are known to be frequently overexpressed in prostate cancer patients, cooperatively down-regulate CIC levels to promote cancer progression. Altogether, we suggest miR-93/miR-106b/miR-375-CIC-CRABP1 as a novel key regulatory axis in prostate cancer progression.
He D, Zhang YW, Zhang NN, et al.Aberrant gene promoter methylation of p16, FHIT, CRBP1, WWOX, and DLC-1 in Epstein-Barr virus-associated gastric carcinomas.
Med Oncol. 2015; 32(4):92 [PubMed
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Alterations in global DNA methylation and specific regulatory gene methylation are frequently found in cancer, but the significance of these epigenetic changes in EBV-associated gastric carcinoma (EBVaGC) remains unclear. We evaluated global DNA methylation status in 49 EBVaGC and 45 EBV-negative gastric carcinoma (EBVnGC) tissue samples and cell lines by 5-methylcytosine immunohistochemical staining and methylation quantification. We determined promoter methylation status and protein expression for the p16, FHIT, CRBP1, WWOX, and DLC-1 genes in tissues and studied the correlation between CpG island methylator phenotype (CIMP) class and clinicopathological characteristics. Changes in gene methylation and mRNA expression in EBVaGC cell line SNU-719 and in EBVnGC cell lines SGC-7901, BGC-823, and AGS were assessed after treatment with 5-aza-2'-deoxycytidine (5-aza-dC), trichostatin A (TSA), or a combination of both, by methylation-specific PCR and quantitative real-time RT-PCR. Global genomic DNA hypomethylation was more pronounced in EBVnGC than in EBVaGC. Promoter methylation of all five genes was more frequent in EBVaGC than in EBVnGC (p < 0.05). p16 and FHIT methylation was reversely correlated with protein expression in EBVaGC. Most (41/49) EBVaGC exhibited CIMP-high (CIMP-H), and the prognosis of CIMP-H patients was significantly worse than that of CIMP-low (p = 0.027) and CIMP-none (p = 0.003) patients. Treatment with 5-aza-dC and/or TSA induced upregulation of RNA expression of all five genes in SNU-719; meanwhile, individual gene expression increased in EBVnGC cell lines. In summary, EBV-induced hypermethylation of p16, FHIT, CRBP1, WWOX, and DLC-1 may contribute to EBVaGC development. Demethylation therapy may represent a novel therapeutic strategy for EBVaGC.
Wang F, Yang Y, Fu Z, et al.Differential DNA methylation status between breast carcinomatous and normal tissues.
Biomed Pharmacother. 2014; 68(6):699-707 [PubMed
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Breast cancer has been considered to be a multifactorial disease with a wide array of well-characterized gene mutations and chromosomal abnormalities. However, it is becoming evident that the onset or development of breast cancer also depends on epigenetic factors, although the mechanisms have not been fully elucidated. We performed a genome-wide analysis of DNA methylation of breast carcinomatous tissues and paired normal tissues to examine the differences in methylation between them. Methylation-specific polymerase chain reaction (MSP) was used to validate the hypermethylated genes screened out by DNA methylation microarray. We found that hypomethylation and hypermethylation occurred in 2753 and 1795 genes, respectively, in breast carcinomatous tissues. Meanwhile, gene ontology analysis and ingenuity pathway analysis revealed the function and pathway of several genes whose methylation status was altered in breast carcinomatous tissues. In addition, we investigated the promoter methylation status of four genes in breast carcinomatous tissue and paired normal tissues (n=30) by MSP. Promoter hypermethylation of CRABP1, HOXB13, IFNGR2, and PIK3C3 was found in 37% (11/30), 23% (7/30), 17% (5/30), and 2% (2/30) of the carcinomas, respectively. Mutation of these four important genes was critical to many types of cancer. Our results suggest that DNA methylation mechanisms may be involved in regulating the occurrence and development of breast cancer.
Kainov Y, Favorskaya I, Delektorskaya V, et al.CRABP1 provides high malignancy of transformed mesenchymal cells and contributes to the pathogenesis of mesenchymal and neuroendocrine tumors.
Cell Cycle. 2014; 13(10):1530-9 [PubMed
] Free Access to Full Article Related Publications
CRABP1 (cellular retinoic acid binding protein 1) belongs to the family of fatty acid binding proteins. Retinoic acid binding is the only known functional activity of this protein. The role of CRABP1 in human carcinogenesis remains poorly understood. Here, for the first time we demonstrated pro-metastatic and pro-tumorigenic activity of CRABP1 in mesenchymal tumors. Further functional analysis revealed that the pro-tumorigenic effect of CRABP1 does not depend on retinoic acid binding activity. These results suggest that CRABP1 could have an alternative intracellular functional activity that contributes to the high malignancy of transformed mesenchymal cells. Microarray analysis detected CRABP1-mediated alterations in the expression of about 100 genes, including those encoding key regulatory proteins. CRABP1 is ubiquitously expressed in monophasic synovial sarcomas, while in biphasic synovial sarcomas it is expressed uniquely by the spindle cells of the aggressive mesenchymal component. High level of CRABP1 expression is associated with lymph node metastasis and poor differentiation/high grade of pancreatic neuroendocrine tumors (pNETs). Presented data suggest CRABP1 as a promising biomarker of pNETs' clinical behavior. Our results give the first evidence of pro-tumorigenic and pro-metastatic activity of CRABP1 in mesenchymal and neuroendocrine tumors.
Berg M, Hagland HR, Søreide KComparison of CpG island methylator phenotype (CIMP) frequency in colon cancer using different probe- and gene-specific scoring alternatives on recommended multi-gene panels.
PLoS One. 2014; 9(1):e86657 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: In colorectal cancer a distinct subgroup of tumours demonstrate the CpG island methylator phenotype (CIMP). However, a consensus of how to score CIMP is not reached, and variation in definition may influence the reported CIMP prevalence in tumours. Thus, we sought to compare currently suggested definitions and cut-offs for methylation markers and how they influence CIMP classification in colon cancer.
METHODS: Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), with subsequent fragment analysis, was used to investigate methylation of tumour samples. In total, 31 CpG sites, located in 8 different genes (RUNX3, MLH1, NEUROG1, CDKN2A, IGF2, CRABP1, SOCS1 and CACNA1G) were investigated in 64 distinct colon cancers and 2 colon cancer cell lines. The Ogino gene panel includes all 8 genes, in addition to the Weisenberger panel of which only 5 of the 8 genes included were investigated. In total, 18 alternative combinations of scoring of CIMP positivity on probe-, gene-, and panel-level were analysed and compared.
RESULTS: For 47 samples (71%), the CIMP status was constant and independent of criteria used for scoring; 34 samples were constantly scored as CIMP negative, and 13 (20%) consistently scored as CIMP positive. Only four of 31 probes (13%) investigated showed no difference in the numbers of positive samples using the different cut-offs. Within the panels a trend was observed that increasing the gene-level stringency resulted in a larger difference in CIMP positive samples than increasing the probe-level stringency. A significant difference between positive samples using 'the most stringent' as compared to 'the least stringent' criteria (20% vs 46%, respectively; p<0.005) was demonstrated.
CONCLUSIONS: A statistical significant variation in the frequency of CIMP depending on the cut-offs and genes included in a panel was found, with twice as many positives samples by least compared to most stringent definition used.
INTRODUCTION: The prognosis of breast cancer is strongly influenced by the developmental stage of the breast when the tumor is diagnosed. Pregnancy-associated breast cancers (PABCs), cancers diagnosed during pregnancy, lactation, or in the first postpartum year, are typically found at an advanced stage, are more aggressive and have a poorer prognosis. Although the systemic and microenvironmental changes that occur during post-partum involution have been best recognized for their role in the pathogenesis of PABCs, epidemiological data indicate that PABCs diagnosed during lactation have an overall poorer prognosis than those diagnosed during involution. Thus, the physiologic and/or biological events during lactation may have a significant and unrecognized role in the pathobiology of PABCs.
METHODS: Syngeneic in vivo mouse models of PABC were used to examine the effects of system and stromal factors during pregnancy, lactation and involution on mammary tumorigenesis. Mammary adipose stromal cell (ASC) populations were isolated from mammary glands and examined by using a combination of in vitro and in vivo functional assays, gene expression analysis, and molecular and cellular assays. Specific findings were further investigated by immunohistochemistry in mammary glands of mice as well as in functional studies using ASCs from lactating mammary glands. Additional findings were further investigated using human clinical samples, human stromal cells and using in vivo xenograft assays.
RESULTS: ASCs present during lactation (ASC-Ls), but not during other mammary developmental stages, promote the growth of carcinoma cells and angiogenesis. ASCs-Ls are distinguished by their elevated expression of cellular retinoic acid binding protein-1 (crabp1), which regulates their ability to retain lipid. Human breast carcinoma-associated fibroblasts (CAFs) exhibit traits of ASC-Ls and express crabp1. Inhibition of crabp1in CAFs or in ASC-Ls abolished their tumor-promoting activity and also restored their ability to accumulate lipid.
CONCLUSIONS: These findings imply that (1) PABC is a complex disease, which likely has different etiologies when diagnosed during different stages of pregnancy; (2) both systemic and local factors are important for the pathobiology of PABCs; and (3) the stromal changes during lactation play a distinct and important role in the etiology and pathogenesis of PABCs that differ from those during post-lactational involution.
BACKGROUND: Diagnosis of ovarian cancer is often delayed because of subtle symptoms and a lack of a specific, sensitive test useful for the general population. The majority of cases are diagnosed at late stages, after the tumor has metastasized and implanted on many other abdominal organs and cavity surfaces. A paucity of prognostic markers makes it difficult to define which tumors will act aggressively and shorten survival. Hence, it is imperative to have new screening tests for diagnosis of ovarian cancer at earlier stages, prior to metastatic progression. Diagnosis at these early stages will dramatically increase the overall survival of women with ovarian cancer.
MATERIAL AND METHODS: Based on previously published literature on proposed molecular cell markers in ovarian carcinoma, we sought to validate the overexpression of two genes (cellular retinoic acid Binding Protein, CRABP-1, and spondin 1) through immunohistochemistry.
RESULTS: We verified the overexpression of spondin 1 in ovarian cancer. Expression of cellular retinoic acid Binding Protein, CRABP-1 in whole ovarian cancer tissue sections was higher than in the TMA tissue cores.
CONCLUSION: Our results thus demonstrate that spondin 1 is a useful marker for ovarian cancer; additionally, the high percentages of tumors that are positive for spondin 1 make it an ideal target for therapy. CRABP-1 was not expressed at high levels in any subtype of ovarian cancer, making it a poor marker.
Honecker F, Rohlfing T, Harder S, et al.Proteome analysis of the effects of all-trans retinoic acid on human germ cell tumor cell lines.
J Proteomics. 2014; 96:300-13 [PubMed
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UNLABELLED: We analysed the effects of all-trans retinoic acid (ATRA) on proliferation and changes in the global proteome of the nullipotent human embryonal carcinoma cell line 2102Ep and the pluripotent cell line NTERA2 cl.D1 (NT2). Differentially expressed proteins were assessed by 2D-PAGE and mass spectrometry, followed by verification and analysis of protein modifications of proteins of the retinoid pathway. We established a proteome map of the germ cell tumor (GCT) cell line NT2 showing neuronal differentiation under ATRA treatment for 7days. Using bioinformatic analyses, we identified functional groups of altered proteins and potentially involved pathways, of which changes to the organization of the cytoskeleton and anti-apoptotic effects were the most prominent. Changes observed in the expression of factors involved in the retinoid pathway under ATRA, namely an upregulation of CRBP and CRABP2, were also reflected in GCT tissues of different histologies, providing further insight into factors involved in the differentiation of these pluripotent tumors.
BIOLOGICAL SIGNIFICANCE: Treatment of NT2 germ cell tumor cells with all-trans retinoic acid (ATRA) is a model to investigate differentiation. We analysed differentially expressed proteins by 2D-PAGE and mass spectrometry and provide a proteome map of NT2 cells under 7days of ATRA. By bioinformatic analyses, functional groups of proteins and involved pathways like changes to the cytoskeleton and anti-apoptotic effects were identified. Factors involved in the retinoid pathway, in particular upregulation of CRBP, CRABP1 and CRABP2, also showed differential expression in tumors with different histological subtypes, which provides insight into gene regulation under induced and spontaneous differentiation in germ cell tumors.
Translocations and amplifications of the mixed lineage leukemia-1 (MLL1) gene are associated with aggressive myeloid and lymphocytic leukemias in humans. MLL1 is a member of the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases, which are required for transcription of genes involved in hematopoiesis and development. MLL1 associates with a subcomplex containing WDR5, RbBP5, Ash2L, and DPY-30 (WRAD), which together form the MLL1 core complex that is required for sequential mono- and dimethylation of H3K4. We previously demonstrated that WDR5 binds the conserved WDR5 interaction (Win) motif of MLL1 in vitro, an interaction that is required for the H3K4 dimethylation activity of the MLL1 core complex. In this investigation, we demonstrate that arginine 3765 of the MLL1 Win motif is required to co-immunoprecipitate WRAD from mammalian cells, suggesting that the WDR5-Win motif interaction is important for the assembly of the MLL1 core complex in vivo. We also demonstrate that peptides that mimic SET1 family Win motif sequences inhibit H3K4 dimethylation by the MLL1 core complex with varying degrees of efficiency. To understand the structural basis for these differences, we determined structures of WDR5 bound to six different naturally occurring Win motif sequences at resolutions ranging from 1.9 to 1.2 Å. Our results reveal that binding energy differences result from interactions between non-conserved residues C-terminal to the Win motif and to a lesser extent from subtle variation of residues within the Win motif. These results highlight a new class of methylation inhibitors that may be useful for the treatment of MLL1-related malignancies.
Fu YS, Wang Q, Ma JX, et al.CRABP-II methylation: a critical determinant of retinoic acid resistance of medulloblastoma cells.
Mol Oncol. 2012; 6(1):48-61 [PubMed
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Medulloblastoma cells exhibit varied responses to therapy by all-trans retinoic acid (RA). The underlying mechanism for such diverse effects however remains largely unclear. In this study, we attempted to elucidate the molecular basis of RA resistance through the study of RA signaling components in both RA-sensitive (Med-3) and RA-resistant (UW228-2 and UW228-3) medulloblastoma cells. The results revealed that RARα/β/γ and RXRα/β/γ were found in the three cell lines. Expression of CRABP-I and CRABP-II was seen in Med-3 cells, up-regulated when treated with RA, but was absent in UW228-2 and UW228-3 cells regardless of RA treatment. Bisulfite sequencing revealed 8 methylated CG sites at the promoter region of CRABP-II in UW228-2 and UW228-3 but not in Med-3 cells. Demethylation by 5-aza-2'-deoxycytidine recovered CRABP-II expression. Upon restoration of CRABP-II expression, both UW228-2 and UW228-3 cells responded to RA treatment by forming neuronal-like differentiation, synaptophysin expression, β-III tubulin upregulation, and apoptosis. Furthermore, CRABP-II specific siRNA reduced RA sensitivity in Med-3 cells. Tissue microarray-based immunohistochemical staining showed variable CRABP-II expression patterns among 104 medulloblastoma cases, ranging from negative (42.3%), partly positive (14.4%) to positive (43.3%). CRABP-II expression was positively correlated with synaptophysin (rs = 0.317; p = 0.001) but not with CRABP-I expression (p > 0.05). In conclusion, aberrant methylation in CRABP-II reduces the expression of CRABP-II that in turn confers RA resistance in medulloblastoma cells. Determination of CRABP-II expression or methylation status may enable a personalized RA therapy in patients with medulloblastomas and other types of cancers.
Chen NN, Li Y, Wu ML, et al.CRABP-II- and FABP5-independent all-trans retinoic acid resistance in COLO 16 human cutaneous squamous cancer cells.
Exp Dermatol. 2012; 21(1):13-8 [PubMed
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The effect of all-trans retinoic acid (ATRA) on cutaneous squamous cell carcinomas (c-SCC) has been poorly described. Because the imbalance of CRABP-II-mediated anticancer signalling and FABP5-mediated growth-promoting signalling was supposed to be related with ATRA sensitivities of cancer cells, COLO16 human c-SCC cell line was selected to check underlying mechanism leading to ATRA resistance by multiple experimental approaches. The results revealed that COLO 16 cells were resistant to 15 μm ATRA treatment. FABP5 as well as the elements related with CRABP-II signalling (CYP26A1, CYP26B1, CRABP-I, RARα/β/γ and RXRα/β/γ) and with FABP5 signalling (PPARβ/δ) were expressed, but CRABP-II was undetectable in COLO 16 cells. 5-Aza treatment enhanced CRABP-II expression but further bisulfite sequencing PCR-DNA sequencing revealed no methylation in CRABP-II promoter region. Transfection of CRABP-II-expressing plasmids or FABP5 siRNA or both successfully manipulated the level(s) of target gene expression but failed to overcome ATRA resistance in the transfectants. In conclusion, CRABP-II and FABP5 expression were imbalanced in ATRA-resistant COLO 16 cells. 5-Aza-enhanced CRABP-II expression and unmethylation in CRABP-II promoter region suggest the methylation of certain CRABP-II regulatory gene(s) in COLO 16 cells. As neither restoration of CRABP-II expression nor the increased CRABP-II versus FABP5 ratio can overcome ATRA resistance of COLO 16 cells, additional ATRA-resistant mechanism(s) may present in human c-SCCs and COLO 16 cells would be of value in addressing this issue.
Chile T, Corrêa-Giannella ML, Fortes MA, et al.Expression of CRABP1, GRP, and RERG mRNA in clinically non-functioning and functioning pituitary adenomas.
J Endocrinol Invest. 2011; 34(8):e214-8 [PubMed
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BACKGROUND: Pituitary tumors account for approximately 10-15% of intracranial neoplasms.
AIM: Using the cDNA microarray method, we have previously compared expression under two distinct conditions: a pool of 4 clinically non-functioning pituitary adenomas (NFPA) and a spinal cord metastasis of a non-functioning pituitary carcinoma, in order to gain biological insights into genomic changes of pituitary neoplasias. In the present study, we further investigated the mRNA expression of 3 selected genes previously described as being involved in other neoplasias based on a series of 60 pituitary adenomas: CRABP1 (cellular retinoic acid binding protein 1), GRP (gastrin-releasing peptide), and RERG (Ras-related, estrogen- regulated, growth inhibitor).
MATERIAL AND METHODS: The expression of CRABP1, GRP, and RERG was determined by quantitative RT-PCR.
RESULTS: A significantly higher content of CRABP1 mRNA was observed in NFPA compared to functioning adenomas, and PRL-secreting adenomas showed a lower expression of this gene compared to normal pituitary. A lower expression of GRP mRNA was detected in NFPA compared to normal pituitary and also to functioning adenomas. RERG mRNA was overexpressed in NFPA in comparison to functioning adenomas and to normal pituitary. Among the functioning adenomas, only the ACTH-secreting adenomas presented a higher expression of RERG mRNA compared to normal pituitary.
CONCLUSIONS: The findings of differential expression of CRABP1 in prolactinomas and of RERG in NFPA compared to normal pituitary suggests that retinoic acid and estrogen receptor, respectively, could be involved in the tumorigenesis of these adenomas subtypes. Additional studies are required to further confirm this hypothesis.
OBJECTIVE: O⁶-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme. MGMT promoter hypermethylation and epigenetic silencing often occur as early events in carcinogenesis. However, prognostic significance of MGMT alterations in colorectal cancer remains uncertain.
METHODS: Utilizing a database of 855 colon and rectal cancers in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we detected MGMT promoter hypermethylation in 325 tumors (38%) by MethyLight and loss of MGMT expression in 37% (247/672) of tumors by immunohistochemistry. We assessed the CpG island methylator phenotype (CIMP) using eight methylation markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and LINE-1 (L1) hypomethylation, TP53 (p53), and microsatellite instability (MSI).
RESULTS: MGMT hypermethylation was not associated with colorectal cancer-specific mortality in univariate or multivariate Cox regression analysis [adjusted hazard ratio (HR) = 1.03; 95% confidence interval (CI), 0.79-1.36] that adjusted for clinical and tumor features, including CIMP, MSI, and BRAF mutation. Similarly, MGMT loss was not associated with patient survival. MGMT loss was associated with G>A mutations in KRAS (p = 0.019) and PIK3CA (p = 0.0031).
CONCLUSIONS: Despite a well-established role of MGMT aberrations in carcinogenesis, neither MGMT promoter methylation nor MGMT loss serves as a prognostic biomarker in colorectal cancer.
Shima K, Nosho K, Baba Y, et al.Prognostic significance of CDKN2A (p16) promoter methylation and loss of expression in 902 colorectal cancers: Cohort study and literature review.
Int J Cancer. 2011; 128(5):1080-94 [PubMed
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A cyclin-dependent kinase inhibitor CDKN2A (p16/Ink4a) is a tumor suppressor and upregulated in cellular senescence. CDKN2A promoter methylation and gene silencing are associated with the CpG island methylator phenotype (CIMP) in colon cancer. However, prognostic significance of CDKN2A methylation or loss of CDKN2A (p16) expression independent of CIMP status remains uncertain. Using a database of 902 colorectal cancers in 2 independent cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we quantified CDKN2A promoter methylation and detected hypermethylation in 269 tumors (30%). By immunohistochemistry, we detected loss of CDKN2A (p16) expression in 25% (200/804) of tumors. We analyzed for LINE-1 hypomethylation and hypermethylation at 7 CIMP-specific CpG islands (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); microsatellite instability (MSI); KRAS, BRAF and PIK3CA mutations; and expression of TP53 (p53), CTNNB1 (β-catenin), CDKN1A (p21), CDKN1B (p27), CCND1 (cyclin D1), FASN (fatty acid synthase) and PTGS2 (cyclooxygenase-2). CDKN2A promoter methylation and loss of CDKN2A (p16) were associated with shorter overall survival in univariate Cox regression analysis [hazard ratio (HR): 1.36, 95% CI: 1.10-1.66, p = 0.0036 for CDKN2A methylation; HR: 1.30, 95% CI: 1.03-1.63, p = 0.026 for CDKN2A (p16) loss] but not in multivariate analysis that adjusted for clinical and tumor variables, including CIMP, MSI and LINE-1 methylation. Neither CDKN2A promoter methylation nor loss of CDKN2A (p16) was associated with colorectal cancer-specific mortality in uni- or multivariate analysis. Despite its well-established role in carcinogenesis, CDKN2A (p16) promoter methylation or loss of expression in colorectal cancer is not independently associated with patient prognosis.
Baba Y, Nosho K, Shima K, et al.PTGER2 overexpression in colorectal cancer is associated with microsatellite instability, independent of CpG island methylator phenotype.
Cancer Epidemiol Biomarkers Prev. 2010; 19(3):822-31 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Prostaglandin-endoperoxide synthase 2 (PTGS2, the HUGO Gene Nomenclature Committee-approved official symbol for cycloxygenase-2, COX-2) and its enzymatic product prostaglandin E2 have critical roles in inflammation and carcinogenesis through the G protein-coupled receptor PTGER2 (EP2). The PTGS2 (COX-2) pathway is a promising target for cancer therapy and chemoprevention. PTGS2 (COX-2) expression in colon cancer has been inversely associated with survival as well as tumoral microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). However, the prognostic significance of PTGER2 expression or its relationship with MSI, CIMP, LINE-1 hypomethylation, or PTGS2 (COX-2) remains uncertain.
METHODS: Using the database of 516 colorectal cancers in two prospective cohort studies with clinical outcome data, we detected PTGER2 overexpression in 169 (33%) tumors by immunohistochemistry. We analyzed MSI using 10 microsatellite markers; CIMP by MethyLight (real-time methylation-specific PCR) on an eight-marker panel [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1]; BRAF, KRAS, PIK3CA, and methylation in LINE-1 by Pyrosequencing; and CTNNB1 (beta-catenin) and TP53 (p53) by immunohistochemistry.
RESULTS: PTGER2 overexpression was positively associated with the mucinous component (P = 0.0016), signet ring cells (P = 0.0024), CIMP-high (P = 0.0023), and MSI-high (P < 0.0001). In multivariate analysis, the significant relationship between PTGER2 and MSI-high persisted (adjusted odds ratio, 2.82; 95% confidence interval, 1.69-4.72; P < 0.0001). PTGER2 was not significantly associated with PTGS2 (COX-2), TP53, or CTNNB1 expression, patient survival, or prognosis.
CONCLUSION: PTGER2 overexpression is associated with MSI-high in colorectal cancer.
IMPACT: Our data imply potential roles of inflammatory reaction by PTGER2 upregulation in carcinogenic process to MSI-high colorectal cancer.
BACKGROUND: Genetic markers for thyroid cancers identified by microarray analysis have offered limited predictive accuracy so far because of the few classes of thyroid lesions usually taken into account. To improve diagnostic relevance, we have simultaneously analyzed microarray data from six public datasets covering a total of 347 thyroid tissue samples representing 12 histological classes of follicular lesions and normal thyroid tissue. Our own dataset, containing about half the thyroid tissue samples, included all categories of thyroid lesions.
METHODOLOGY/PRINCIPAL FINDINGS: Classifier predictions were strongly affected by similarities between classes and by the number of classes in the training sets. In each dataset, sample prediction was improved by separating the samples into three groups according to class similarities. The cross-validation of differential genes revealed four clusters with functional enrichments. The analysis of six of these genes (APOD, APOE, CLGN, CRABP1, SDHA and TIMP1) in 49 new samples showed consistent gene and protein profiles with the class similarities observed. Focusing on four subclasses of follicular tumor, we explored the diagnostic potential of 12 selected markers (CASP10, CDH16, CLGN, CRABP1, HMGB2, ALPL2, ADAMTS2, CABIN1, ALDH1A3, USP13, NR2F2, KRTHB5) by real-time quantitative RT-PCR on 32 other new samples. The gene expression profiles of follicular tumors were examined with reference to the mutational status of the Pax8-PPARgamma, TSHR, GNAS and NRAS genes.
CONCLUSION/SIGNIFICANCE: We show that diagnostic tools defined on the basis of microarray data are more relevant when a large number of samples and tissue classes are used. Taking into account the relationships between the thyroid tumor pathologies, together with the main biological functions and pathways involved, improved the diagnostic accuracy of the samples. Our approach was particularly relevant for the classification of microfollicular adenomas.
Banz C, Ungethuem U, Kuban RJ, et al.The molecular signature of endometriosis-associated endometrioid ovarian cancer differs significantly from endometriosis-independent endometrioid ovarian cancer.
Fertil Steril. 2010; 94(4):1212-7 [PubMed
] Free Access to Full Article Related Publications
OBJECTIVE: To determine whether endometriosis-associated endometrioid cancer (EAOC) is a specific entity compared with endometrioid cancer not associated with endometriosis (OC).
DESIGN: Case-control study.
SETTING: University hospital research laboratory.
PATIENT(S): Seven patients with endometriosis-associated ovarian cancer EAOC and five patients each with OC, ovarian endometriosis, and benign ovaries.
INTERVENTION(S): Ovarian tissue samples were collected from surgical procedures.
MAIN OUTCOME MEASURE(S): We hybridized cRNA samples to the Affymetrix HG-U133A microarray chip. Representative genes were validated by real time polymerase chain reaction.
RESULT(S): We identified two main groups of genes: The first group contained the genes SICA2, CCL14, and TDGF1. These genes were equally regulated in endometriosis and EAOC but not in OC and benign ovaries. The second group contained the genes StAR, SPINT1, Keratin 8, FoxM1B, FOLR1, CRABP1, and Claudin 7. They were equally regulated in EAOC and OC but not in ovarian endometriosis and benign ovaries.
CONCLUSION(S): That the first group is composed of the cytokines SICA2 and CCL14 and the growth factor TDGF1 indicates that the regulation of the autoimmune system and of inflammatory cytokines may be very important in the etiology of endometriosis and EAOC. That the second group is composed of genes that play a central role in cell-cell interaction, differentiation, and cell proliferation indicates that they may be important in the development of ovarian cancer in women with endometriosis.
Transcription in eukaryotic genomes depends on enzymes that regulate the degree of histone H3 lysine 4 (H3K4) methylation. The mixed lineage leukemia protein-1 (MLL1) is a member of the SET1 family of H3K4 methyltransferases and is frequently rearranged in acute leukemias. Despite sequence comparisons that predict that SET1 family enzymes should only monomethylate their substrates, mono-, di-, and trimethylation of H3K4 has been attributed to SET1 family complexes in vivo and in vitro. To better understand this paradox, we have biochemically reconstituted and characterized a five-component 200-kDa MLL1 core complex containing human MLL1, WDR5, RbBP5, Ash2L, and DPY-30. We demonstrate that the isolated MLL1 SET domain is a slow monomethyltransferase and that tyrosine 3942 of MLL1 prevents di- and trimethylation of H3K4. In contrast, a complex containing the MLL1 SET domain, WDR5, RbBP5, Ash2L, and DPY-30, displays a marked approximately 600-fold increase in enzymatic activity but only to the dimethyl form of H3K4. Single turnover kinetic experiments reveal that the reaction leading to H3K4 dimethylation involves the transient accumulation of a monomethylated species, suggesting that the MLL1 core complex uses a non-processive mechanism to catalyze multiple lysine methylation. We have also discovered that the non-SET domain components of the MLL1 core complex possess a previously unrecognized methyltransferase activity that catalyzes H3K4 dimethylation within the MLL1 core complex. Our results suggest that the mechanism of multiple lysine methylation by the MLL1 core complex involves the sequential addition of two methyl groups at two distinct active sites within the complex.
PURPOSE: DNA methyltransferase-3B (DNMT3B) plays an important role in de novo CpG island methylation. Dnmt3b can induce colon tumor in mice with methylation in specific CpG islands. We hypothesized that cellular DNMT3B level might influence the occurrence of widespread CpG island methylation (i.e., the CpG island methylator phenotype, CIMP) in colon cancer.
EXPERIMENTAL DESIGN: Utilizing 765 colorectal cancers in two cohort studies, we detected DNMT3B expression in 116 (15%) tumors by immunohistochemistry. We assessed microsatellite instability, quantified DNA methylation in repetitive long interspersed nucleotide element-1 (LINE-1) by Pyrosequencing, eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by real-time PCR (MethyLight).
RESULTS: Tumoral DNMT3B overexpression was significantly associated with CIMP-high [> or =6/8 methylated CIMP-specific promoters; odds ratio (OR), 3.34; 95% confidence interval, 2.11-5.29; P < 0.0001]. The relations between DNMT3B and methylation in 16 individual CpG islands varied substantially (OR, 0.80-2.96), suggesting variable locus-to-locus specificities of DNMT3B activity. DNMT3B expression was not significantly related with LINE-1 hypomethylation. In multivariate logistic regression, the significant relation between DNMT3B and CIMP-high persisted (OR, 2.39; 95% confidence interval, 1.11-5.14; P = 0.026) after adjusting for clinical and other molecular features, including p53, beta-catenin, LINE-1, microsatellite instability, KRAS, PIK3CA, and BRAF. DNMT3B expression was unrelated with patient outcome, survival, or prognosis.
CONCLUSIONS: Tumoral DNMT3B overexpression is associated with CIMP-high in colorectal cancer. Our data support a possible role of DNMT3B in nonrandom de novo CpG island methylation leading to colorectal cancer.
The class III histone deacetylase SIRT1 (sir2) is important in epigenetic gene silencing. Inhibition of SIRT1 reactivates silenced genes, suggesting a possible therapeutic approach of targeted reversal of aberrantly silenced genes. In addition, SIRT1 may be involved in the well-known link between obesity, cellular energy balance and cancer. However, a comprehensive study of SIRT1 using human cancer tissue with clinical outcome data is currently lacking, and its prognostic significance is uncertain. Using the database of 485 colorectal cancers in two independent prospective cohort studies, we detected SIRT1 overexpression in 180 (37%) tumors by immunohistochemistry. We examined its relationship to the CpG island methylator phenotype (CIMP), related molecular events, clinical features including body mass index, and patient survival. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by MethyLight. SIRT1 overexpression was associated with CIMP-high (> or =6 of 8 methylated CIMP-specific promoters, P=0.002) and microsatellite instability (MSI)-high phenotype (P<0.0001). In both univariate and multivariate analyses, SIRT1 overexpression was significantly associated with the CIMP-high MSI-high phenotype (multivariate odds ratio, 3.20; 95% confidence interval, 1.35-7.59; P=0.008). In addition, mucinous component (P=0.01), high tumor grade (P=0.02), and fatty acid synthase overexpression (P=0.04) were significantly associated with SIRT positivity in multivariate analysis. SIRT1 was not significantly related with age, sex, tumor location, stage, signet ring cells, cyclooxygenase-2 (COX-2), LINE-1 hypomethylation, KRAS, BRAF, BMI, PIK3CA, HDAC, p53, beta-catenin, COX-2, or patient prognosis. In conclusion, SIRT1 expression is associated with CIMP-high MSI-high colon cancer, suggesting involvement of SIRT1 in gene silencing in this unique tumor subtype.
Lee HS, Kim BH, Cho NY, et al.Prognostic implications of and relationship between CpG island hypermethylation and repetitive DNA hypomethylation in hepatocellular carcinoma.
Clin Cancer Res. 2009; 15(3):812-20 [PubMed
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PURPOSE: This study aims to determine the relationship between CpG island DNA hypermethylation and global genomic DNA hypomethylation and their prognostic implications in hepatocellular carcinoma. The association of DNA methylation changes with clinicopathologic factors and the chronological ordering of DNA methylation changes along multistep hepatocarcinogenesis were also assessed.
EXPERIMENTAL DESIGN: Hepatocellular carcinoma (n = 20) and nonneoplastic liver samples (n = 72) were analyzed for their methylation status at 41 CpG island loci and 3 repetitive DNA elements (LINE-1, ALU, and SAT2) using MethyLight or combined bisulfite restriction analysis. After selection of 19 CpG island loci showing cancer-specific DNA methylation, another set of 99 hepatocellular carcinoma samples was analyzed for these loci.
RESULTS: The number of methylated genes in hepatocellular carcinoma was significantly higher in hepatocellular carcinoma patients with a cirrhotic liver than in hepatocellular carcinoma patients with a noncirrhotic liver (9.9 versus 7.0, P = 0.001). Hepatocellular carcinoma from female patients showed a higher number of methylated genes than hepatocellular carcinoma from male patients (11.2 versus 8.4, P = 0.006). The genes CRABP1 and SYK showed significant association between CpG island hypermethylation and patients' poor survival. SAT2 hypomethylation occurred earlier than LINE-1 or ALU hypomethylation along the multistep hepatocarcinogenesis. Depending on the type of CpG island locus, a direct, inverse, or no relationship between CpG island hypermethylation and repetitive DNA hypomethylation was observed in hepatocellular carcinomas.
CONCLUSION: The varying relationships between the hypermethylation of individual CpG island loci and the hypomethylation of repetitive elements suggests that they are not mechanically linked. SYK and CRABP1 hypermethylation may serve as useful tumor markers for prognostication of hepatocellular carcinoma patients.
BACKGROUND: Multiple epigenetic and genetic changes have been reported in colorectal tumors, but few of these have clinical impact. This study aims to pinpoint epigenetic markers that can discriminate between non-malignant and malignant tissue from the large bowel, i.e. markers with diagnostic potential. The methylation status of eleven genes (ADAMTS1, CDKN2A, CRABP1, HOXA9, MAL, MGMT, MLH1, NR3C1, PTEN, RUNX3, and SCGB3A1) was determined in 154 tissue samples including normal mucosa, adenomas, and carcinomas of the colorectum. The gene-specific and widespread methylation status among the carcinomas was related to patient gender and age, and microsatellite instability status. Possible CIMP tumors were identified by comparing the methylation profile with microsatellite instability (MSI), BRAF-, KRAS-, and TP53 mutation status.
RESULTS: The mean number of methylated genes per sample was 0.4 in normal colon mucosa from tumor-free individuals, 1.2 in mucosa from cancerous bowels, 2.2 in adenomas, and 3.9 in carcinomas. Widespread methylation was found in both adenomas and carcinomas. The promoters of ADAMTS1, MAL, and MGMT were frequently methylated in benign samples as well as in malignant tumors, independent of microsatellite instability. In contrast, normal mucosa samples taken from bowels without tumor were rarely methylated for the same genes. Hypermethylated CRABP1, MLH1, NR3C1, RUNX3, and SCGB3A1 were shown to be identifiers of carcinomas with microsatellite instability. In agreement with the CIMP concept, MSI and mutated BRAF were associated with samples harboring hypermethylation of several target genes.
CONCLUSION: Methylated ADAMTS1, MGMT, and MAL are suitable as markers for early tumor detection.
OBJECTIVES: We have previously reported that loss in expression of a protein considered critical for vitamin A homeostasis, cellular retinol-binding protein 1 (CRBP1), is an early event in ovarian carcinogenesis. The aim of the present study was to determine if loss of vitamin A metabolism also occurs early in ovarian oncogenesis.
METHODS: We assessed CRBP1 expression by immunohistochemistry in ovaries prophylactically removed from women with a genetic risk for ovarian cancer. Furthermore, we investigated the ability of normal, immortalized but nontumorigenic, and tumorigenic human ovarian epithelial cells to synthesize retinoic acid and retinaldehyde when challenged with a physiological dose of retinol, and determined expression levels of the retinoid-related genes, RARalpha, RXRalpha, CRABP1, CRABP2, RALDH1 and RALDH2 in these cells.
RESULTS: Immunohistochemistry revealed loss of CRBP1 expression in potentially preneoplastic lesions in prophylactic oophorectomies. HPLC analysis of vitamin A metabolism showed production of retinoic acid in four independent, normal human ovarian surface epithelial (HOSE) cell cultures upon exposure to retinol. However, only one of two SV40-immortalized HOSE cell lines made RA, while none of the ovarian carcinoma cell lines produced detectable RA due to complete loss of RALDH2.
CONCLUSIONS: The impaired conversion of retinol to RA in ovarian cancer cells and decreased CRBP1 protein expression in prophylactic oophorectomies support our hypothesis that concomitant losses of vitamin A metabolism and CRBP1 expression contribute to ovarian oncogenesis.
Nosho K, Shima K, Kure S, et al.JC virus T-antigen in colorectal cancer is associated with p53 expression and chromosomal instability, independent of CpG island methylator phenotype.
Neoplasia. 2009; 11(1):87-95 [PubMed
] Free Access to Full Article Related Publications
JC virus has a transforming gene encoding JC virus T-antigen (JCVT). JCVT may inactivate wild-type p53, cause chromosomal instability (CIN), and stabilize beta-catenin. A link between JCVT and CpG island methylator phenotype (CIMP) has been suggested. However, no large-scale study has examined the relations of JCVT with molecular alterations, clinical outcome, or prognosis in colon cancer. We detected JCVT expression (by immunohistochemistry) in 271 (35%) of 766 colorectal cancers. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other loci (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, WRN) by MethyLight. We examined loss of heterozygosity in 2p, 5q, 17q, and 18q. JCVT was significantly associated with p53 expression (P < .0001), p21 loss (P < .0001), CIN (>/=2 chromosomal segments with LOH; P < .0001), nuclear beta-catenin (P = .006), LINE-1 hypomethylation (P = .002), and inversely with CIMP-high (P = .0005) and microsatellite instability (MSI) (P < .0001), but not with PIK3CA mutation. In multivariate logistic regression analysis, the associations of JCVT with p53 [adjusted odds ratio (OR), 8.45; P < .0001], CIN (adjusted OR, 2.53; P = .003), cyclin D1 (adjusted OR, 1.57; P = .02), LINE-1 hypomethylation (adjusted OR, 1.97 for a 30% decline as a unit; P = .03), BRAF mutation (adjusted OR, 2.20; P = .04), and family history of colorectal cancer (adjusted OR, 0.64; P = .04) remained statistically significant. However, JCVT was no longer significantly associated with CIMP, MSI, beta-catenin, or cyclooxygenase-2 expression in multivariate analysis. JCVT was unrelated with patient survival. In conclusion, JCVT expression in colorectal cancer is independently associated with p53 expression and CIN, which may lead to uncontrolled cell proliferation.
Gupta A, Kessler P, Rawwas J, Williams BRRegulation of CRABP-II expression by MycN in Wilms tumor.
Exp Cell Res. 2008; 314(20):3663-8 [PubMed
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Cellular retinoic acid binding protein II (CRABP-II) is overexpressed in a wide variety of cancers. Previously we have shown that CRABP-II expression levels are also elevated in neuroblastoma and Wilms tumors. To elucidate the molecular mechanisms underlying the abnormal expression of CRABP-II in Wilms tumor, we studied the expression of MycN and CRABP-II in these tumor samples. Our data revealed that CRABP-II is overexpressed in Wilms tumor compared to normal adjacent non-neoplastic tissue and its levels are even higher in late stage tumors. Its expression correlates with MycN expression in tumors. The tumors that do not express MycN have no CRABP-II expression. The expression of CRABP-II is also regulated by methylation and its promoter is unmethylated in tumors. Knockdown of MycN by small interfering RNA leads to downregulation of CRABP-II. Thus our results suggest that both MycN and DNA methylation are responsible for CRABP-II expression in pediatric tumors and demethylation of CRABP-II may be an early event in tumor development.
Parker H, An Q, Barber K, et al.The complex genomic profile of ETV6-RUNX1 positive acute lymphoblastic leukemia highlights a recurrent deletion of TBL1XR1.
Genes Chromosomes Cancer. 2008; 47(12):1118-25 [PubMed
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The ETV6-RUNX1 fusion is the molecular consequence of the t(12;21)(p13;q22) seen in approximately 25% of children with acute lymphoblastic leukemia (ALL). Studies have shown that the fusion alone is insufficient for the initiation of leukemia; additional genetic changes are required. Genomic profiling identified copy number alterations at high frequencies in these patients. Focal deletions of TBL1XR1 were observed in 15% of cases; 3 patients exhibited deletions distal to the gene. Fluorescence in situ hybridization confirmed these deletions and quantitative RT-PCR showed that the TBL1XR1 gene was significantly under-expressed. TBL1XR1 is a key component of the SMRT and N-CoR compressor complexes, which control hormone-receptor mediated gene expression. Differential expression of the retinoic acid target genes, RARB, CRABP1, and CRABP2, indicated that deletion of TBL1XR1 compromised the function of SMRT/N-CoR in the appropriate control of gene expression. This study identifies deletions of TBL1XR1 as a recurrent abnormality in ETV6-RUNX1 positive ALL. We provide evidence that implicates this deletion in the inappropriate control of gene expression in these patients. The target of the interaction between TBL1XR1 and the signaling pathways described here may be exploited in cancer therapy.
Synovial sarcoma is a rare sarcoma of unknown histologic origin. We previously reported the gene expression profile of synovial sarcoma was closely related to that of malignant peripheral nerve sheath tumors, and the fibroblast growth factor (FGF) signal was one of the main growth signals in synovial sarcoma. Here we further demonstrate the neural origin of synovial sarcoma using primary tumors and cell lines. The expression of neural tissue-related genes was confirmed in synovial sarcoma tumor tissues, but the expression of some genes was absent in synovial sarcoma cell lines. Treatment of synovial sarcoma cell lines with BMP4 or FGF2 enhanced or restored the expression of neural tissue-related genes and induced a neuron-like morphology with positive Tuj-1 expression. Treatment with all-trans-retinoic acid also induced the expression of neural tissue-related genes in association with growth inhibition, which was not observed in other cell lines except a malignant peripheral nerve sheath tumor cell line. A growth-inhibitory effect of all-trans-retinoic acid was also observed for xenografted tumors in athymic mice. The simultaneous treatment with FGF signal inhibitors enhanced the growth-inhibitory effect of all-trans-retinoic acid, suggesting the combination of growth signaling inhibition and differentiation induction could be a potential molecular target for treating synovial sarcoma.