Research IndicatorsGraph generated 06 August 2015 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 06 August, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
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
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: ELF3 (cancer-related)
Montavon G, Jauquier N, Coulon A, et al.Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells.
Oncotarget. 2014; 5(12):4452-66 [PubMed
] Free Access to Full Article Related Publications
The anaplastic lymphoma kinase (ALK) gene is overexpressed, mutated or amplified in most neuroblastoma (NB), a pediatric neural crest-derived embryonal tumor. The two most frequent mutations, ALK-F1174L and ALK-R1275Q, contribute to NB tumorigenesis in mouse models, and cooperate with MYCN in the oncogenic process. However, the precise role of activating ALK mutations or ALK-wt overexpression in NB tumor initiation needs further clarification. Human ALK-wt, ALK-F1174L, or ALK-R1275Q were stably expressed in murine neural crest progenitor cells (NCPC), MONC-1 or JoMa1, immortalized with v-Myc or Tamoxifen-inducible Myc-ERT, respectively. While orthotopic implantations of MONC- 1 parental cells in nude mice generated various tumor types, such as NB, osteo/ chondrosarcoma, and undifferentiated tumors, due to v-Myc oncogenic activity, MONC-1-ALK-F1174L cells only produced undifferentiated tumors. Furthermore, our data represent the first demonstration of ALK-wt transforming capacity, as ALK-wt expression in JoMa1 cells, likewise ALK-F1174L, or ALK-R1275Q, in absence of exogenous Myc-ERT activity, was sufficient to induce the formation of aggressive and undifferentiated neural crest cell-derived tumors, but not to drive NB development. Interestingly, JoMa1-ALK tumors and their derived cell lines upregulated Myc endogenous expression, resulting from ALK activation, and both ALK and Myc activities were necessary to confer tumorigenic properties on tumor-derived JoMa1 cells in vitro.
Aberrant regulation of the Wnt/β-catenin pathway plays important roles in colorectal carcinogenesis, with over 90% of cases of sporadic colon cancer featuring β-catenin accumulation. While ubiquitination-mediated degradation is widely accepted as a major route for β-catenin protein turnover, little is known about the regulation of β-catenin in transcriptional level. Here we show that Elf3, a member of the E-twenty-six family of transcription factors, drives β-catenin transactivation and associates with poor survival of colorectal cancer (CRC) patients. We first found recurrent amplification and upregulation of Elf3 in CRC tissues, and further Gene Set Enrichment Analysis identified significant association between Elf3 expression and activity of WNT/β-catenin pathway. Chromatin immunoprecipitation and electrophoretic mobility shift assay consistently revealed that Elf3 binds to and transactivates β-catenin promoter. Ectopic expression of Elf3 induces accumulation of β-catenin in both nucleus and cytoplasm, causing subsequent upregulation of several effector genes including c-Myc, VEGF, CCND1, MMP-7 and c-Jun. Suppressing Elf3 in CRC cells attenuates β-catenin signaling and decreases cell proliferation, migration and survival. Targeting Elf3 in xenograft tumors suppressed tumor progression in vivo. Taken together, our data identify Elf3 as a pivotal driver for β-catenin signaling in CRC, and highlight potential prognostic and therapeutic significance of Elf3 in CRC.
Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.
Emori M, Tsukahara T, Murase M, et al.High expression of CD109 antigen regulates the phenotype of cancer stem-like cells/cancer-initiating cells in the novel epithelioid sarcoma cell line ESX and is related to poor prognosis of soft tissue sarcoma.
PLoS One. 2013; 8(12):e84187 [PubMed
] Free Access to Full Article Related Publications
Epithelioid sarcoma (ES) is a relatively rare, highly malignant soft tissue sarcoma. The mainstay of treatment is resection or amputation. Currently other therapeutic options available for this disease are limited. Therefore, a novel therapeutic option needs to be developed. In the present study, we established a new human ES cell line (ESX) and analyzed the characteristics of its cancer stem-like cells/cancer-initiating cells (CSCs/CICs) based on ALDH1 activity. We demonstrated that a subpopulation of ESX cells with high ALDH1 activity (ALDH(high) cells) correlated with enhanced clonogenic ability, sphere-formation ability, and invasiveness in vitro and showed higher tumorigenicity in vivo. Next, using gene expression profiling, we identified CD109, a GPI-anchored protein upregulated in the ALDH(high) cells. CD109 mRNA was highly expressed in various sarcoma cell lines, but weakly expressed in normal adult tissues. CD109-positive cells in ESX predominantly formed spheres in culture, whereas siCD109 reduced ALDH1 expression and inhibited the cell proliferation in vitro. Subsequently, we evaluated the expression of CD109 protein in 80 clinical specimens of soft tissue sarcoma. We found a strong correlation between CD109 protein expression and the prognosis (P = 0.009). In conclusion, CD109 might be a CSC/CIC marker in epithelioid sarcoma. Moreover, CD109 is a promising prognostic biomarker and a molecular target of cancer therapy for sarcomas including ES.
BRIP1 is a DNA helicase that directly interacts with the C-terminal BRCT repeat of the breast cancer susceptibility protein BRCA1 and plays an important role in BRCA1-dependent DNA repair and DNA damage-induced checkpoint control. Recent studies implicate BRIP1 as a moderate/low-penetrance breast cancer susceptibility gene. However, the phenotypic effects of BRIP1 dysfunction and its role in breast cancer tumorigenesis remain unclear. To explore the function of BRIP1 in acinar morphogenesis of mammary epithelial cells, we generated BRIP1-knockdown MCF-10A cells by short hairpin RNA (shRNA)-mediated RNA interference and examined its effect in a three-dimensional culture model. Genome-wide gene expression profiling by microarray and quantitative RT-PCR were performed to identify alterations in gene expression in BRIP1-knockdown cells compared with control cells. The microarray data were further investigated using the pathway analysis and Gene Set Enrichment Analysis (GSEA) for pathway identification. BRIP1 knockdown in non-malignant MCF-10A mammary epithelial cells by RNA interference induced neoplastic-like changes such as abnormal cell adhesion, increased cell proliferation, large and irregular-shaped acini, invasive growth, and defective lumen formation. Differentially expressed genes, including MCAM, COL8A1, WIPF1, RICH2, PCSK5, GAS1, SATB1, and ELF3, in BRIP1-knockdown cells compared with control cells were categorized into several functional groups, such as cell adhesion, polarity, growth, signal transduction, and developmental process. Signaling-pathway analyses showed dysregulation of multiple cellular signaling pathways, involving LPA receptor, Myc, Wnt, PI3K, PTEN as well as DNA damage response, in BRIP1-knockdown cells. Loss of BRIP1 thus disrupts normal mammary morphogenesis and causes neoplastic-like changes, possibly via dysregulating multiple cellular signaling pathways functioning in the normal development of mammary glands.
Nam JM, Jeon KH, Kwon H, et al.Dithiiranylmethyloxy azaxanthone shows potent anti-tumor activity via suppression of HER2 expression and HER2-mediated signals in HER2-overexpressing breast cancer cells.
Eur J Pharm Sci. 2013; 50(2):181-90 [PubMed
] Related Publications
Dithiiranylmethyloxy azaxanthone (CHO10), which was discovered by screening compounds in a reporter gene assay, inhibited the ESX-Sur2 interaction in a dose-dependent manner with potency similar to canertinib. The intervention of CHO10 during the ESX-Sur2 interaction caused down-regulation of both HER2 gene amplification and HER2 protein expression, which led to the attenuation of HER2-mediated downstream signal cascades and autocrine cell growth in SK-BR-3 cells, which are HER2 overexpressing breast cancer cells. The cell growth inhibitory activity of CHO10 was more potent in HER2-overexpressing breast cancer cells (AU-565, BT474 and SK-BR-3) than in HER2-negative cells (HEK293) and breast cancer cells (MCF-7) that express a basal level of HER2. Treatment with CHO10 in combination with tamoxifen sensitized BT474 cells, tamoxifen-resistant ER-positive breast cancer cell line, toward chemotherapeutic. The anti-tumor activity of CHO10 was validated by the significant reduction in tumor size of NCI-H460 or DLD-1 subcutaneously implanted xenograft tumors through treatment with 1mg/kg five times every other 2days.
EGF receptor (EGFR) is elevated in more than 90% of head and neck squamous cell carcinoma (HNSCC). However, a majority of patients with HNSCC do not respond to anti-EGFR therapeutics. Insensitivity to EGFR inhibitors may be due to kinase-independent actions of EGFR and/or activation of Her2. Strategies to reduce EGFR and Her2 protein levels in concert may be an optimal approach to enhance the efficacy of current anti-EGFR molecules. In this study, knockdown of epithelial-restricted with serine box (ESX) decreased EGFR and Her2 promoter activity, expression, and levels. ESX was elevated in primary HNSCC tumors and associated with increased EGFR and Her2. Genetic ablation of ESX decreased EGFR and Her2 levels and enhanced the antiproliferative effects of EGFR/Her2 tyrosine kinase inhibitors (TKI), lapatinib and afatinib. Biphenyl isoxazolidine, a novel small-molecule ESX inhibitor, reduced EGFR and Her2 levels and potentiated the antiproliferative efficacy of afatinib. Single-agent biphenyl isoxazolidine retarded the in vivo tumorigenicity of CAL27 cells. Importantly, the combination of biphenyl isoxazolidine and afatinib was significantly superior in vivo and resulted in a 100% response rate with a 94% reduction in tumor volume. Targeting EGFR/Her2 levels with an ESX inhibitor and EGFR/Her2 kinase activity with a TKI simultaneously is a highly active therapeutic approach to manage HNSCC. Our work provides evidence to support the further development of ESX inhibitors as an adjuvant to enhance the response rate of patients with HNSCC to current anti-EGFR/Her2 therapeutics.
Longoni N, Sarti M, Albino D, et al.ETS transcription factor ESE1/ELF3 orchestrates a positive feedback loop that constitutively activates NF-κB and drives prostate cancer progression.
Cancer Res. 2013; 73(14):4533-47 [PubMed
] Related Publications
Chromosomal translocations leading to deregulated expression of ETS transcription factors are frequent in prostate tumors. Here, we report a novel mechanism leading to oncogenic activation of the ETS factor ESE1/ELF3 in prostate tumors. ESE1/ELF3 was overexpressed in human primary and metastatic tumors. It mediated transforming phenotypes in vitro and in vivo and induced an inflammatory transcriptome with changes in relevant oncogenic pathways. ESE1/ELF3 was induced by interleukin (IL)-1β through NF-κB and was a crucial mediator of the phenotypic and transcriptional changes induced by IL-1β in prostate cancer cells. This linkage was mediated by interaction of ESE1/ELF3 with the NF-κB subunits p65 and p50, acting by enhancing their nuclear translocation and transcriptional activity and by inducing p50 transcription. Supporting these findings, gene expression profiling revealed an enrichment of NF-κB effector functions in prostate cancer cells or tumors expressing high levels of ESE1/ELF3. We observed concordant upregulation of ESE1/ELF3 and NF-κB in human prostate tumors that was associated with adverse prognosis. Collectively, our results define an important new mechanistic link between inflammatory signaling and the progression of prostate cancer.
AbdulMajeed AA, Dalley AJ, Farah CSLoss of ELF3 immunoexpression is useful for detecting oral squamous cell carcinoma but not for distinguishing between grades of epithelial dysplasia.
Ann Diagn Pathol. 2013; 17(4):331-40 [PubMed
] Related Publications
Early diagnosis and targeted therapy are crucial to mitigating the morbidity and mortality of oral squamous cell carcinoma. Among the potentially malignant oral disorders, epithelial dysplasia has known association with malignant transformation, but defensible gradation of dysplasia severity presents unmet challenges. Published microarray data has denoted dysregulation of CLSP, ELF3, IFI44, USP18, and CXCL13 genes in potentially malignant oral disorders. The present study investigated the diagnostic potential of these gene products to grade oral epithelial dysplasia severity. Archived biopsies from independent patient cohorts comprised "training" (n=107) and "test" (n=278) sample sets. Immunoreactivity for candidate markers was determined in the "training" set of normal oral mucosa (NOM), mild dysplasia (MD), moderate to severe dysplasia, and oral squamous cell carcinoma (OSCC). The diagnostic potential of ELF3 immunoscoring to improve detection and severity gradation of epithelial dysplasia was assessed with the "test" set. A reciprocal relationship between disease severity and immunoreactivity score for CLSP and ELF3 was observed (MD/NOM to OSCC: P<.08, Mann-Whitney U test), whereas elevated IFI44 immunostaining was present for OSCC compared to MD/NOM (P<.08, Mann-Whitney U test). Loss of ELF3 immunostaining effectively distinguished OSCC from non-malignant tissues (sensitivity=0.81; specificity=0.56; area under the curve [AUC]=0.68) but did not distinguish dysplasia from NOM (sensitivity=0.55; specificity=0.40; AUC=0.47) or moderate to severe dysplasia from MD (sensitivity=0.63; specificity=0.51; AUC=0.57). The results confirm via immunohistochemistry the relevance of published CLSP, ELF3, and IFI44 (but not USP18 or CXCL13) gene expression data to potentially malignant oral lesion severity. Loss of ELF3 immunostaining discriminated OSCC from dysplasia but was unreliable for grading dysplasia severity.
Clinical observations spanning almost half a century have demonstrated a consistent association of type 1 Gaucher disease (GD1) and cancers. However, the cellular and molecular bases of the association are not understood. Gaucher disease (GD) is a lysosomal storage disorder due to an inherited deficiency of acid β-glucosidase that underlies the accumulation of glucosylceramide in lysosomes of mononuclear phagocytes and immune dysregulation. The overall cancer risk is markedly increased in GD, and the determinants of malignancy in a subset of patients with GD1 are not known. The association of GD and cancer is most striking for hematological malignancies, with the risk for multiple myeloma estimated at almost 37-fold compared to the general population; some studies have also suggested increased cancer risk for non-hematological malignancies. There is no association of overall severity of GD to risk of cancer, although there is an increased prevalence of splenectomy among patients exhibiting the GD/cancer phenotype. Moreover, there appears to be an increased incidence of multiple consecutive cancers in individual patients. Several factors could contribute to cancer development in GD, including polarization of macrophages to the alternatively activated phenotype, chronic inflammation, chronic B-cell stimulation, splenectomy, hyperferritinemia, lysosomal dysfunction, and endoplasmic reticulum stress. Recent studies have highlighted T-cell dysfunction and modifier genes contributing to an increased cancer risk in GD. Macrophage-targeted enzyme replacement therapy (ERT) reverses systemic features of GD1; while cancer risk appears to be reduced in the era of ERT, it is not known whether this is a direct effect of therapy. Delineation of the mechanisms underlying the increased cancer risk in GD will provide additional novel insights into the role of lipids and macrophages in cancer pathogenesis and, moreover, have the potential to reveal novel therapeutic targets.
The androgen receptor (AR) has a critical role in the development and progression of prostate cancer (PC) and is a major therapeutic target in this disease. The transcriptional activity of AR is modulated by the coregulators with which it interacts, and consequently deregulation of cofactor expression and/or activity impacts the expression of genes whose products can have a role in PC pathogenesis. Here we report that E74-like factor 3 (ELF3), a member of the ETS family of transcription factors, is a repressor of AR transcriptional activity. Exogenous expression of ELF3 represses AR transcriptional activity when assessed using reporter-based transfection assays or when evaluated on endogenous AR target genes. Conversely, ELF3 knock down increases the AR transcriptional activity. Biochemical dissection of this activity indicates that it results from the physical interaction between ELF3 and AR and that this interaction inhibits the recruitment of AR to specific androgen response elements within target gene promoters. Significantly, we observed that depletion of ELF3 expression in LNCaP cells promotes cell migration, whereas increased ELF3 expression severely inhibits tumor growth in vitro and in a mouse xenograft model. Taken together, these results suggest that modulation of ELF3 expression and/or AR/ELF3 interaction may have utility in the treatment of PC.
Mesquita B, Lopes P, Rodrigues A, et al.Frequent copy number gains at 1q21 and 1q32 are associated with overexpression of the ETS transcription factors ETV3 and ELF3 in breast cancer irrespective of molecular subtypes.
Breast Cancer Res Treat. 2013; 138(1):37-45 [PubMed
] Related Publications
Several ETS transcription factors are involved in the pathogenesis of human cancers by different mechanisms. As gene copy number gain/amplification is an alternative mechanism of oncogenic activation and 1q gain is the most common copy number change in breast carcinoma, we investigated how that genomic change impacts in the expression of the three 1q ETS family members ETV3, ELK4, and ELF3. We have first evaluated 141 breast carcinomas for genome-wide copy number changes by chromosomal CGH and showed that 1q21 and 1q32 were the two chromosome bands with most frequent genomic copy number gains. Second, we confirmed by FISH with locus-specific BAC clones that cases showing 1q gain/amplification by CGH showed copy number increase of the ETS genes ETV3 (located in 1q21~23), ELF3, and ELK4 (both in 1q32). Third, gene expression levels of the three 1q ETS genes, as well as their potential targets MYC and CRISP3, were evaluated by quantitative real-time PCR. We here show for the first time that the most common genomic copy number gains in breast cancer, 1q21 and 1q32, are associated with overexpression of the ETS transcription factors ETV3 and ELF3 (but not ELK4) at these loci irrespective of molecular subtypes. Among the three 1q ETS genes, ELF3 has a relevant role in breast carcinogenesis and is also the most likely target of the 1q copy number increase. The basal-like molecular subtype presented the worst prognosis regarding disease-specific survival, but no additional prognostic value was found for 1q copy number status or ELF3 expression. In addition, we show that there is a correlation between the expression of the oncogene MYC, irrespectively of copy number gain at its loci in 8q24, and the expression of both the transcriptional repressor ETV3 and the androgen respondent ELK4.
Nakarai C, Osawa K, Matsubara N, et al.Significance of ELF3 mRNA expression for detection of lymph node metastases of colorectal cancer.
Anticancer Res. 2012; 32(9):3753-8 [PubMed
] Related Publications
BACKGROUND: Lymph node (LN) evaluation is an important factor for the prognosis of colorectal cancer (CRC). The purpose of our study was to investigate the effectiveness of E74-like factor 3 (ELF3) and carcinoembryonic antigen (CEA) as useful markers to detect LN metastases in CRC.
MATERIALS AND METHODS: We examined the mRNA expression of ELF3 and CEA in LNs and tissues from 22 patients with CRC and in controls with ulcerative colitis (UC) by real-time quantitative reverse transcription polymerase chain reaction, as well as by hematoxylin-eosin staining.
RESULTS: ELF3 and CEA expression showed statistically significant differences among four LN groups: LNs from patients with CRC categorized into three Dukes' stages and LNs from patients with UC (p<0.001 and p<0.001, respectively). We found a statistical correlation between the expression levels of both markers in patients with CRC compared with each Dukes' stage.
CONCLUSION: ELF3, as a gene marker, may be sufficiently practical to detect LN metastases of CRC, rather than CEA.
Tanaka S, Miyagi S, Sashida G, et al.Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia.
Blood. 2012; 120(5):1107-17 [PubMed
] Related Publications
EZH2, a catalytic component of the polycomb repressive complex 2, trimethylates histone H3 at lysine 27 (H3K27) to repress the transcription of target genes. Although EZH2 is overexpressed in various cancers, including some hematologic malignancies, the role of EZH2 in acute myeloid leukemia (AML) has yet to be examined in vivo. In the present study, we transformed granulocyte macrophage progenitors from Cre-ERT;Ezh2(flox/flox) mice with the MLL-AF9 leukemic fusion gene to analyze the function of Ezh2 in AML. Deletion of Ezh2 in transformed granulocyte macrophage progenitors compromised growth severely in vitro and attenuated the progression of AML significantly in vivo. Ezh2-deficient leukemic cells developed into a chronic myelomonocytic leukemia-like disease with a lower frequency of leukemia-initiating cells compared with the control. Chromatin immunoprecipitation followed by sequencing revealed a significant reduction in the levels of trimethylation at H3K27 in Ezh2-deficient leukemic cells, not only at Cdkn2a, a known major target of Ezh2, but also at a cohort of genes relevant to the developmental and differentiation processes. Overexpression of Egr1, one of the derepressed genes in Ezh2-deficient leukemic cells, promoted the differentiation of AML cells profoundly. Our findings suggest that Ezh2 inhibits differentiation programs in leukemic stem cells, thereby augmenting their leukemogenic activity.
Oliver JR, Kushwah R, Hu JMultiple roles of the epithelium-specific ETS transcription factor, ESE-1, in development and disease.
Lab Invest. 2012; 92(3):320-30 [PubMed
] Related Publications
The E26 transformation-specific (ETS) family of transcription factors comprises of 27 and 26 members in humans and mice, respectively, which are known to regulate many different biological processes, including cell proliferation, cell differentiation, embryonic development, neoplasia, hematopoiesis, angiogenesis, and inflammation. The epithelium-specific ETS transcription factor-1 (ESE-1) is a physiologically important ETS transcription factor, which has been shown to play a role in the pathogenesis of various diseases, and was originally characterized as having an epithelial-restricted expression pattern, thus placing it within the epithelium-specific ETS subfamily. Despite a large body of published work on ETS biology, much remains to be learned about the precise functions of ESE-1 and other epithelium-specific ETS factors in regulating diverse disease processes. Clues as to the specific function of ESE-1 in the setting of various diseases can be obtained from studies aimed at examining the expression of putative target genes regulated by ESE-1. Thus, this review will focus primarily on the various roles of ESE-1 in different pathophysiological processes, including regulation of epithelial cell differentiation during both intestinal development and lung regeneration; regulation of dendritic cell-driven T-cell differentiation during allergic airway inflammation; regulation of mammary gland development and breast cancer; and regulation of the effects of inflammatory stimuli within the setting of synovial joint and vascular inflammation. Understanding the exact mechanisms by which ESE-1 regulates these processes can have important implications for the treatment of a wide range of diseases.
Moncada-Vélez M, Vélez-Ortega A, Orrego J, et al.Somatic mosaicism caused by monoallelic reversion of a mutation in T cells of a patient with ADA-SCID and the effects of enzyme replacement therapy on the revertant phenotype.
Scand J Immunol. 2011; 74(5):471-81 [PubMed
] Free Access to Full Article Related Publications
Patients with adenosine deaminase (ADA) deficiency exhibit spontaneous and partial clinical remission associated with somatic reversion of inherited mutations. We report a child with severe combined immunodeficiency (T-B- SCID) due to ADA deficiency diagnosed at the age of 1 month, whose lymphocyte counts including CD4+ and CD8+ T and NK cells began to improve after several months with normalization of ADA activity in Peripheral blood lymphocytes (PBL), as a result of somatic mosaicism caused by monoallelic reversion of the causative mutation in the ADA gene. He was not eligible for haematopoietic stem cell transplantation (HSCT) or gene therapy (GT); therefore he was placed on enzyme replacement therapy (ERT) with bovine PEG-ADA. The follow-up of metabolic and immunologic responses to ERT included gradual improvement in ADA activity in erythrocytes and transient expansion of most lymphocyte subsets, followed by gradual stabilization of CD4+ and CD8+ T (with naïve phenotype) and NK cells, and sustained expansion of TCRγδ+ T cells. This was accompanied by the disappearance of the revertant T cells as shown by DNA sequencing from PBL. Although the patient's clinical condition improved marginally, he later developed a germinal cell tumour and eventually died at the age of 67 months from sepsis. This case adds to our current knowledge of spontaneous reversion of mutations in ADA deficiency and shows that the effects of the ERT may vary among these patients, suggesting that it could depend on the cell and type in which the somatic mosaicism is established upon reversion.
Saghir FS, Rose IM, Dali AZ, et al.Gene expression profiling and cancer-related pathways in type I endometrial carcinoma.
Int J Gynecol Cancer. 2010; 20(5):724-31 [PubMed
] Related Publications
INTRODUCTION: Malignant transformation of type I endometrium involves alteration in gene expression with subsequent uncontrolled proliferation of altered cells.
OBJECTIVE: The main objective of the present study was to identify the cancer-related genes and gene pathways in the endometrium of healthy and cancer patients.
MATERIALS AND METHODS: Thirty endometrial tissues from healthy and type I EC patients were subjected to total RNA isolation. The RNA samples with good integrity number were hybridized to a new version of Affymetrix Human Genome GeneChip 1.0 ST array. We analyzed the results using the GeneSpring 9.0 GX and the Pathway Studio 6.1 software. For validation assay, quantitative real-time polymerase chain reaction was used to analyze 4 selected genes in normal and EC tissue.
RESULTS: Of the 28,869 genes profiled, we identified 621 differentially expressed genes (2-fold) in the normal tissue and the tumor. Among these genes, 146 were up-regulated and 476 were down-regulated in the tumor as compared with the normal tissue (P < 0.001). Up-regulated genes included the v-erb-a erythroblastic leukemia viral oncogene homolog 3 (ErbB3), ErbB4, E74-like factor 3 (ELF3), and chemokine ligand 17 (CXCL17). The down-regulated genes included signal transducer and activator transcription 5B (STAT5b), transforming growth factor A receptor III (TGFA3), caveolin 1 (CAV1), and protein kinase C alpha (PKCA). The gene set enrichment analysis showed 10 significant gene sets with related genes (P < 0.05). The quantitative polymerase chain reaction of 4 selected genes using similar RNA confirmed the microarray results (P < 0.05).
CONCLUSIONS: Identification of molecular pathways with their genes related to type I EC contribute to the understanding of pathophysiology of this cancer, probably leading to identifying potential biomarkers of the cancer.
BACKGROUND: The cancer stem cell (CSC) hypothesis proposes that a population of tumor cells bearing stem cell properties is responsible for the origin and maintenance of tumors. Normal and cancer stem cells possess the ability to grow in vitro as self-renewing spheres, but the molecular basis of this phenotype remains largely unknown. We intended to establish a comprehensive culture system to grow prostatospheres (PSs) from both cancer cell lines and patient tumors. We then used gene expression microarrays to gain insight on the molecular pathways that sustain the PS tumor initiating cell (TIC) phenotype.
RESULTS: Traditional stem cell medium (SCM) supplemented with KnockoutSR (KO) allows the propagation of monoclonal PSs from cell lines and primary cells. PSs display gene expression and tumorigenicity hallmarks of TICs. Gene expression analysis defined a gene signature composed of 66 genes that characterize LNCaP and patient PSs. This set includes novel prostate TIC growth factors (NRP1, GDF1, JAG1), proteins implicated in cell adhesion and cytoskeletal maintenance, transcriptional regulators (MYCBP, MYBL1, ID1, ID3, FOS, ELF3, ELF4, KLF2, KLF5) and factors involved in protein biosynthesis and metabolism. Meta-analysis in Oncomine reveals that some of these genes correlate with prostate cancer status and/or progression. Reporter genes and inhibitors indicate that the Notch pathway contributes to prostatosphere growth.
CONCLUSIONS: We have developed a model for the culture of PSs, and provide a genomic profile that support CSCs identity. This signature identifies novel markers and pathways that are predicted to correlate with prostate cancer evolution.
Lo SM, Stein P, Mullaly S, et al.Expanding spectrum of the association between Type 1 Gaucher disease and cancers: a series of patients with up to 3 sequential cancers of multiple types--correlation with genotype and phenotype.
Am J Hematol. 2010; 85(5):340-5 [PubMed
] Free Access to Full Article Related Publications
In Gaucher disease (GD), inherited deficiency of lysosomal glucocerebrosidase due to mutations in GBA1 gene results in accumulation of glucosylceramide in tissue macrophages, systemic macrophage activation, and a complex multisystemic phenotype. We and others have reported an increased risk of multiple myeloma and other malignancies in non-neuronopathic Type 1 GD (GD1). Here, we describe a subset of GD1 patients with multiple malignancies. In our cohort of 403 patients with GD1, nine patients (2.2%) developed two or three different types of cancers either consecutively or simultaneously. Patients were characterized by age at diagnosis of GD1, GBA1 genotype, disease severity, age at cancer diagnosis, enzyme replacement therapy (ERT) status, and splenectomy status. Of the nine patients, six developed two types of malignancies and three had three cancers each. Overall, the hematologic malignancies comprised lymphoma/leukemia (4) and multiple myeloma (4). Nonhematologic malignancies included colon (2), lung (2), thyroid (2), and prostate cancer (1). Of the seven patients who received ERT, the first cancer was diagnosed before initiation of ERT in all but one. Asplenic patients were more likely to have single or multiple cancers compared with patients with intact spleens (P < 0.0072 and P < 0.0203, respectively). Our data strengthen the association of GD1 and cancer and suggest that patients may be at risk of developing multiple malignancies. We found an association between splenectomy and multiple cancers in GD1. It will be of interest to determine whether timely ERT and declining rates of splenectomy will translate into declining rates of multiple and single cancers.
Xia X, Zhang S, Yu Y, et al.Effects of estrogen replacement therapy on estrogen receptor expression and immunoregulatory cytokine secretion in surgically induced menopausal women.
J Reprod Immunol. 2009; 81(1):89-96 [PubMed
] Related Publications
To investigate the effect of oral and transdermal estrogen replacement therapy (ERT) on the expression of different estrogen receptor (ER) subtypes and the secretion of immunoregulatory cytokines, we performed a clinical investigation on previously healthy women who had undergone a total hysterectomy and bilateral salpingo-oopherectomy. These women were randomly distributed into two groups: an oral ERT group and transdermal ERT group. Before and after ERT, the serum levels of estradiol (E2) and follicle stimulating hormone (FSH) were measured, ERalpha and ERbeta expression of peripheral blood T lymphocytes was tested, and secretion of specific immunoregulatory cytokines (IFNgamma, IL-2 and IL-4) by T lymphocytes was examined. Our results confirm that for both groups, the serum E2 level was increased after ERT (P<0.01) and the serum FSH level was decreased after ERT (P<0.01), with no significant difference in hormone levels between the two groups. ERalpha expression by T lymphocytes was significantly higher after ERT than before (P<0.01) in both groups. Levels of type 1 cytokines (IL-2 and IFNgamma), which were secreted by T helper 1 (Th1), after ERT were substantially decreased. The level of type 2 cytokine (IL-4), which were secreted by T helper 2 (Th2), was significantly increased after ERT (P<0.01 for the oral group and P<0.05 for the transdermal group). In summary, both oral and transdermal ERT increased serum E2 levels, decreased serum FSH levels and relieved the effects of peri-menopausal symptoms. These data suggest that both oral and transdermal ERT act to improve the balance of Th1/Th2 cytokines by the effects of estrogen potentially acting in T lymphocytes mainly through ERalpha.
PURPOSE: Atypical protein kinase Ciota (PKCiota) is an oncogene in non-small cell lung cancer (NSCLC). Here, we identify four functional gene targets of PKCiota in lung adenocarcinoma (LAC), the most prominent form of NSCLC.
EXPERIMENTAL DESIGN: Three independent public domain gene expression data sets were interrogated to identify genes coordinately expressed with PKCiota in primary LAC tumors. Results were validated by QPCR in an independent set of primary LAC tumors. RNAi-mediated knockdown of PKCiota and the target genes was used to determine whether expression of the identified genes was regulated by PKCiota, and whether these target genes play a role in anchorage-independent growth and invasion of LAC cells.
RESULTS: Meta-analysis identified seven genes whose expression correlated with PKCiota in primary LAC. Subsequent QPCR analysis confirmed coordinate overexpression of four genes (COPB2, ELF3, RFC4, and PLS1) in an independent set of LAC samples. RNAi-mediated knockdown showed that PKCiota regulates expression of all four genes in LAC cells, and that the four PKCiota target genes play an important role in the anchorage-independent growth and invasion of LAC cells. Meta-analysis of gene expression data sets from lung squamous cell, breast, colon, prostate, and pancreas carcinomas, as well as glioblastoma, revealed that a subset of PKCiota target genes, particularly COPB2 and RFC4, correlate with PKCiota expression in many tumor types.
CONCLUSION: Meta-analysis of public gene expression data are useful in identifying novel gene targets of oncogenic PKCiota signaling. Our data indicate that both common and cell type-specific signaling mechanisms contribute to PKCiota-dependent transformation.
van Dekken H, Tilanus HW, Hop WC, et al.Array comparative genomic hybridization, expression array, and protein analysis of critical regions on chromosome arms 1q, 7q, and 8p in adenocarcinomas of the gastroesophageal junction.
Cancer Genet Cytogenet. 2009; 189(1):37-42 [PubMed
] Related Publications
Survival rates of adenocarcinomas of the gastroesophageal junction (GEJ) are low, because these tumors are generally in an advanced stage by the time they are detected. Chromosomal regions 1q32, 7q21, and 8p22 display critical alterations in GEJ cancers; however, the genes underlying alterations in these genomic areas are largely unknown. To delineate overexpressed genes, we performed array comparative genomic hybridization (aCGH) and mRNA expression analysis of 15 GEJ adenocarcinoma samples using a fine-tiling cDNA array covering chromosome segments 1q31.3~q41 (193.9-215.8 Mb: 21.9 Mb), 7q11.23~q22.1 (72.3-103.0 Mb: 30.7 Mb), and 8p23.1~p21.3 (11.1-20.7 Mb: 9.6 Mb). Based on a mRNA overexpression criterion, 11 genes were selected: ELF3 and SLC45A3 on 1q; CLDN12, CDK6, SMURF1, ARPC1B, ZKSCAN1, MCM7, and COPS6 on 7q; and FDFT1 and CTSB on 8p. The protein expression levels were subsequently determined by immunohistochemical analysis of the cancer samples. There was a significant correlation between genomic amplification, mRNA, and protein expression or overexpression for CDK6, a cell cycle regulator on 7q21.2 (92.1 Mb; P<0.01); other genes showed less stringent associations. In conclusion, using a straightforward approach we constructed a targeted gene profile for GEJ adenocarcinomas.
Quinn MC, Filali-Mouhim A, Provencher DM, et al.Reprogramming of the transcriptome in a novel chromosome 3 transfer tumor suppressor ovarian cancer cell line model affected molecular networks that are characteristic of ovarian cancer.
Mol Carcinog. 2009; 48(7):648-61 [PubMed
] Related Publications
Tumor suppression as a consequence of the transfer of chromosome 3p fragments was previously observed in a novel epithelial ovarian cancer (EOC) OV-90 cell line model harboring loss of 3p. Microarray analysis revealed that tumor suppression was associated with a modified transcriptome. To investigate the relevance of the altered transcriptome, the differentially expressed genes identified by Affymetrix analysis in the 3p transfer studies, were integrated with a comparative microarray analysis of normal ovarian surface epithelial (NOSE) cells and malignant ovarian (TOV) cancers. Data from 219 significantly differentially expressed genes exhibited patterns in the direction predicted by the analysis of 3p transfer study. The 30 genes with the highest statistically significant differences (P < 1 x 10(-8)) in expression were found consistently differentially expressed between NOSE and TOV samples. The investigation of these genes in benign serous ovarian tumors and EOC cell lines also exhibited predictable expression patterns. Within the group of differentially expressed genes were SPARC, DAB2, CP, EVI1, ELF3, and EHD2, known to play a role in ovarian cancer, genes implicated in other cancers, such as GREM1 and GLIPR1, as well as genes not previously reported in a cancer context such as AKAP2 and ATAD4. A number of the differentially expressed genes are implicated in the TGF-beta signaling pathway. These findings suggest that the reprogramming of the transcriptome that occurred as a consequence of the chromosome 3 transfer and tumor suppression affected molecular networks that are characteristic of ovarian carcinogenesis thus validating our novel ovarian cancer cell line model.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to prevent colorectal tumorigenesis. Although antitumor effects of NSAIDs are mainly due to inhibition of cyclooxygenase activity, there is increasing evidence that cyclooxygenase-independent mechanisms may also play an important role. The early growth response-1 (EGR-1) gene is a member of the immediate-early gene family and has been identified as a tumor suppressor gene. Tolfenamic acid is a NSAID that exhibits anticancer activity in a pancreatic cancer model. In the present study, we investigated the anticancer activity of tolfenamic acid in human colorectal cancer cells. Tolfenamic acid treatment inhibited cell growth and induced apoptosis as measured by caspase activity and bioelectric impedance. Tolfenamic acid induced EGR-1 expression at the transcription level, and analysis of the EGR-1 promoter showed that a putative ETS-binding site, located at -400 and -394 bp, was required for activation by tolfenamic acid. The electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed that this sequence specifically bound to the ETS family protein epithelial-specific ETS-1 (ESE-1) transcription factor. Tolfenamic acid also facilitated translocation of endogenous and exogenous ESE-1 to the nucleus in colorectal cancer cells, and gene silencing using ESE-1 small interfering RNA attenuated tolfenamic acid-induced EGR-1 expression and apoptosis. Overexpression of EGR-1 increased apoptosis and decreased bioelectrical impedance, and silencing of endogenous EGR-1 prevented tolfenamic acid-induced apoptosis. These results show that activation of ESE-1 via enhanced nuclear translocation mediates tolfenamic acid-induced EGR-1 expression, which plays a critical role in the activation of apoptosis.
Ets transcription factors comprise a large family of sequence-specific regulators of gene expression with important and diverse roles in development and disease. Most Ets family members are expressed in the developing and/or mature intestine, frequently in a compartment-specific and temporally dynamic manner. However, with the exception of the highly expressed Elf3, involved in embryonic epithelial differentiation, little is known about Ets functions in intestinal development and homeostasis. Ets factors show altered expression in colon cancer, where they regulate pathways relevant to tumor progression. Ets factors also likely act as important modifiers of non-neoplastic intestinal disease by regulating pathways relevant to tissue injury and repair. Despite a large body of published work on Ets biology, much remains to be learned about the precise functions of this large and diverse gene family in intestinal morphogenesis, homeostasis, and both neoplastic and non-neoplastic pathology.
BACKGROUND: Epigenetic changes are emerging as one of the most important events in carcinogenesis. Two alterations in the pattern of DNA methylation in breast cancer (BC) have been previously reported; active estrogen receptor-alpha (ER-alpha) is associated with decreased methylation of ER-alpha target (ERT) genes, and polycomb group target (PCGT) genes are more likely than other genes to have promoter DNA hypermethylation in cancer. However, whether DNA methylation in normal unrelated cells is associated with BC risk and whether these imprints can be related to factors which can be modified by the environment, is unclear.
METHODOLOGY/PRINCIPAL FINDINGS: Using quantitative methylation analysis in a case-control study (n = 1,083) we found that DNA methylation of peripheral blood cell DNA provides good prediction of BC risk. We also report that invasive ductal and invasive lobular BC is characterized by two different sets of genes, the latter particular by genes involved in the differentiation of the mesenchyme (PITX2, TITF1, GDNF and MYOD1). Finally we demonstrate that only ERT genes predict ER positive BC; lack of peripheral blood cell DNA methylation of ZNF217 predicted BC independent of age and family history (odds ratio 1.49; 95% confidence interval 1.12-1.97; P = 0.006) and was associated with ER-alpha bioactivity in the corresponding serum.
CONCLUSION/SIGNIFICANCE: This first large-scale epigenotyping study demonstrates that DNA methylation may serve as a link between the environment and the genome. Factors that can be modulated by the environment (like estrogens) leave an imprint in the DNA of cells that are unrelated to the target organ and indicate the predisposition to develop a cancer. Further research will need to demonstrate whether DNA methylation profiles will be able to serve as a new tool to predict the risk of developing chronic diseases with sufficient accuracy to guide preventive measures.
Iwai S, Amekawa S, Yomogida K, et al.ESE-1 inhibits the invasion of oral squamous cell carcinoma in conjunction with MMP-9 suppression.
Oral Dis. 2008; 14(2):144-9 [PubMed
] Related Publications
OBJECTIVES: Matrix metalloproteinases (MMPs) regulated by ets transcription factors facilitate carcinoma cell invasion. An ets family member, ESE-1, is expressed specifically in epithelial tissues, but its association with MMPs is obscure. In this study, we investigated whether ESE-1 regulates invasion of oral squamous cell carcinoma (SCC) via transcriptional activity of MMP-9.
METHODS: HSC-3 and KB were used as human oral SCC lines. The expression of ESE-1 and MMP-9 was detected by in situ hybridization and immunohistochemistry. Invasion assay, gelatin zymography and Northern blotting were used to detect the invasion activity, the gelatinolytic activity and the expression of MMP-9 in the ESE-1 transfectants. Luciferase assays and mutation analysis were used for the transcriptional analysis of MMP-9 promoter region by ESE-1.
RESULTS: ESE-1 was expressed in the intermediate layer but not in the invasive area, in which MMP-9 was expressed, in the oral SCC tissues. ESE-1 suppressed invasion activity and 92 kDa gelatinolytic activity in HSC-3 as a result of transfection. ESE-1 regulates MMP-9 expression in a negative manner and the ets binding site on the MMP-9 promoter contributed to suppression by ESE-1.
CONCLUSIONS: These findings indicate that ESE-1 negatively regulates the invasion of oral SCC via transcriptional suppression of MMP-9.
Tschoep K, Kohlmann A, Schlemmer M, et al.Gene expression profiling in sarcomas.
Crit Rev Oncol Hematol. 2007; 63(2):111-24 [PubMed
] Related Publications
Sarcomas are a heterogeneous group of malignant mesenchymal tumors of difficult classification. There is considerable variability in both histological appearance and responsiveness to therapy. Their overall poor clinical prognosis is reflected by the fact that >65% of patients suffering retroperitoneal soft tissue sarcoma die within 5 years [Heslin MJ, et al. Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol 1997;15(8):2832-9]. A greater understanding of the biology of sarcomas is needed in order to increase the potential for identifying new therapeutic targets and strategies. Microarray analysis permits a global approach to gene expression analysis of thousands of genes at the same time and has proven to be useful for further molecular characterization of tumor tissue and cell lines. This article provides a comprehensive review of possible new biomarkers identified in gene expression studies of sarcomas. These markers give new insight into the pathogenesis of sarcomas, such as malignant fibrous histiocytoma [Lee YF, et al. Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling. Br J Cancer 2003;88(4):510-5], allow a further subclassifcation of tumors like calponin-positive and calponin-negative leiomyosarcoma, or may help to predict treatment responsiveness and prognosis in patients based on an individual gene expression pattern. In some studies candidate targets for possible new treatment strategies were identified. For instance newly identified markers such as ERBB2 [Allander SV, et al. Expression profiling of synovial sarcoma by cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation. Am J Pathol 2002;161(5):1587-95] and EGFR [Nielsen TO, et al. Molecular characterization of soft tissue tumours: a gene expression study. Lancet 2002;359(9314):1301-7] might lead to the possible therapeutic use of Trastuzumab, Gefitinib or Cetuximab in synovial sarcoma, comparable to the use of tyrosine kinase inhibitor STI (Gleevec) that is the standard treatment today of CD117-positive gastrointestinal stromal tumors.
Manavathi B, Rayala SK, Kumar RPhosphorylation-dependent regulation of stability and transforming potential of ETS transcriptional factor ESE-1 by p21-activated kinase 1.
J Biol Chem. 2007; 282(27):19820-30 [PubMed
] Related Publications
Differential phosphorylation of transcription factors by signal transduction pathways play an important role in regulation of gene expression and functions. ESE-1 is an epithelium-specific ETS transcription factor that transforms human breast epithelial cells through a serine- and aspartic acid-rich domain (SAR) by an unknown cytoplasmic mechanism. Here we found that a signaling kinase, p21-activated kinase-1 (Pak1), interacts with and phosphorylates ESE-1. Interestingly, Pak1 selectively phosphorylates ESE-1 at Ser(207), which is located within the SAR domain. A S207A substitution in ESE-1 reduced its ability to transform breast cancer cells. We also found that ESE-1 is a labile protein and by interacting with F-box-binding protein beta-TrCP, undergoes ubiquitin-dependent proteolysis. Intriguingly, Pak1 phosphorylation inactive mutant ESE1-S207A is more unstable than either wild-type ESE-1 or its Pak1 phosphorylation mimetic mutant, i.e. ESE1-S207E. These findings provide novel insights into the mechanism of transformation potential of ESE-1 and discovered that ESE-1 functions are coordinately regulated by Pak1 phosphorylation and beta-TrCP-dependent ubiquitin-proteasome pathways.
Goulet AC, Watts G, Lord JL, Nelson MAProfiling of selenomethionine responsive genes in colon cancer by microarray analysis.
Cancer Biol Ther. 2007; 6(4):494-503 [PubMed
] Related Publications
High-selenium containing yeast is being evaluated in clinical trials against colon polyp recurrence. However, the molecular targets for the anticancer effects of selenium remain unclear. Previous studies by our group demonstrated that selenomethionine-induced growth arrest appears to be mediated by activation of ERK and subsequent phosphorylation of RSK and histone H3. These results suggest that selenomethionine can alter gene expression. In the present study, we have used cDNA microarrays to determine whether gene expression differences exist in HCT116 colon cancer cells treated with selenomethionine. These experiments reveal statistically significant expression changes for 50 genes. Genes we found to increase with selenomethionine treatment include KLK6, ATOX1, SGK, GJB2, DAP-1, PLAU, VIM, DPYSL2, STC2 and PXN. Conversely, genes downregulated by selenomethionine include PRKACB, LIM, DEPP, MYC, CDH5, ELF3, VSNL1, SAT and EGLN3. Further analysis of those genes using chromatin immunoprecipitation experiments showed that phosphorylated histone H3 on serine 10 bound to the GJB2 promoter (connexin 26) or the serum glucocorticoid kinase promoter is increased with selenomethionine treatment. Cells overexpressing CX26 or DAP-1 displayed a reduced number of colonies which suggests that these two genes could play a functional role in the growth inhibitory effects of selenomethionine. These data support the notion that selenomethionine-induced growth inhibition is associated with global changes in gene expression. They also demonstrate that selenomethionine can modify chromatin state to alter gene transcription. Finally, our studies provide a practical foundation for the further development of biomarkers to monitor the efficacy of selenomethionine in clinical trials.