Gene Summary

Gene:TLE1; transducin-like enhancer of split 1 (E(sp1) homolog, Drosophila)
Aliases: ESG, ESG1, GRG1
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:transducin-like enhancer protein 1
Source:NCBIAccessed: 07 August, 2015


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

Research Indicators

Publications Per Year (1990-2015)
Graph generated 07 August 2015 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 07 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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

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

Latest Publications: TLE1 (cancer-related)

Yao X, Ireland SK, Pham T, et al.
TLE1 promotes EMT in A549 lung cancer cells through suppression of E-cadherin.
Biochem Biophys Res Commun. 2014; 455(3-4):277-84 [PubMed] Article available free on PMC after 12/12/2015 Related Publications
The Groucho transcriptional corepressor TLE1 protein has recently been shown to be a putative lung specific oncogene, but its underlying oncogenic activity in lung cancer has not been fully elucidated. In this report, we investigated whether TLE1 regulates lung cancer aggressiveness using the human lung adenocarcinoma cell line A549 as a model system. Through a combination of genetic approaches, we found that TLE1 potentiates epithelial-to-mesenchymal transition (EMT) in A549 cells in part through suppression of the tumor suppressor gene E-cadherin. Exogenous expression of TLE1 in A549 cells resulted in heightened EMT phenotypes (enhanced fibroblastoid morphology and increased cell migratory potential) and in molecular alterations characteristic of EMT (downregulation of the epithelial marker E-cadherin and upregulation of the mesenchymal marker Vimentin). Conversely, downregulation of endogenous TLE1 expression in these cells resulted in reversal of basal EMT characterized by a cuboidal-like epithelial cell phenotype, reduced cell motility, and upregulated E-cadherin expression. Mechanistic studies showed that TLE1 suppresses E-cadherin expression at the transcriptional level in part by recruiting histone deacetylase (HDAC) activity to the E-cadherin promoter. Consistently, the HDAC inhibitor TSA partially reversed the TLE1-induced E-cadherin downregulation and cell migration, suggesting a role for HDACs in TLE1-mediated transcriptional repression of E-cadherin and EMT function. These findings uncover a novel role of TLE1 in regulating EMT in A549 cells through its repressive effect on E-cadherin and provide a mechanism for TLE1 oncogenic activity in lung cancer.

Yao X, Jennings S, Ireland SK, et al.
The anoikis effector Bit1 displays tumor suppressive function in lung cancer cells.
PLoS One. 2014; 9(7):e101564 [PubMed] Article available free on PMC after 12/12/2015 Related Publications
The mitochondrial Bit1 (Bcl-2 inhibitor of transcription 1) protein is a part of an apoptotic pathway that is uniquely regulated by integrin-mediated attachment. As an anoikis effector, Bit1 is released into the cytoplasm following loss of cell attachment and induces a caspase-independent form of apoptosis. Considering that anoikis resistance is a critical determinant of transformation, we hypothesized that cancer cells may circumvent the Bit1 apoptotic pathway to attain anchorage-independence and tumorigenic potential. Here, we provide the first evidence of the tumor suppressive effect of Bit1 through a mechanism involving anoikis induction in human lung adenocarcinoma derived A549 cells. Restitution of Bit1 in anoikis resistant A549 cells is sufficient to induce detachment induced-apoptosis despite defect in caspase activation and impairs their anchorage-independent growth. Conversely, stable downregulation of Bit1 in these cells significantly enhances their anoikis resistance and anchorage-independent growth. The Bit1 knockdown cells exhibit significantly enhanced tumorigenecity in vivo. It has been previously shown that the nuclear TLE1 corepressor is a putative oncogene in lung cancer, and we show here that TLE1 blocks Bit1 mediated anoikis in part by sequestering the pro-apoptotic partner of Bit1, the Amino-terminal Enhancer of Split (AES) protein, in the nucleus. Taken together, these findings suggest a tumor suppressive role of the caspase-independent anoikis effector Bit1 in lung cancer. Consistent with its role as a tumor suppressor, we have found that Bit1 is downregulated in human non-small cell lung cancer (NSCLC) tissues.

Williams JS, Xiao Y, Brownell I
Low pH reprograms somatic murine cells into pluripotent stem cells: a novel technique with therapeutic implications.
Cancer Biol Ther. 2014; 15(6):675-7 [PubMed] Article available free on PMC after 12/12/2015 Related Publications
Induced pluripotent stem cells (iPSCs) are somatic cells that are reprogrammed into a state resembling embryonic stem cells (ESCs). iPSCs represent a promising technology with applications in cancer research, yet current methods used to generate iPSCs limit their translation to clinical use. In a recent Nature article, Obokata et al. detail a novel technique to generate pluripotent murine cells called stimulus-triggered acquisition of pluripotency (STAP). STAP eliminates the need for exogenous expression of reprogramming factors used in previous iPSC technologies, instead transforming somatic cells to pluripotency using physical and chemical stimuli. The authors found that STAP cells are generated at a 10-fold higher efficiency than prior iPSC technologies. STAP cells display several features of pluripotency, namely the expression of pluripotency-related genes (Oct4, Nanog, Sox2, Ecat1, Esg1, and Dax1), the ability to form teratomas in vivo, and the ability to produce viable, fertile mice in blastocyst complementation assays. Here, we review these findings on STAP and contrast it to previous iPSC technologies, while noting the potential of this method to generate autologous anti-tumor immune cells for cancer therapy.

Valente AL, Tull J, Zhang S
Specificity of TLE1 expression in unclassified high-grade sarcomas for the diagnosis of synovial sarcoma.
Appl Immunohistochem Mol Morphol. 2013; 21(5):408-13 [PubMed] Related Publications
Expression of the transducin-like enhancer of split 1 (TLE1) by immunohistochemistry (IHC) has been widely used as a biomarker for the diagnosis of synovial sarcoma. Although TLE1 expression can be identified in more than 90% of synovial sarcomas, positive staining has been reported in up to one third of nonsynovial sarcomas, including peripheral nerve sheath tumors and neoplasms of fibrous and adipose tissues. The low specificity of this test in soft tissue tumors raises concern on its clinical application as a diagnostic biomarker. As synovial sarcoma is frequent among the differential diagnosis of unclassified high-grade sarcomas, and considering that the specificity of TLE1 antibody in this tumor group remains unclear, we evaluated TLE1 expression by IHC in 42 unclassified high-grade sarcomas. SS18 (SYT) gene break-apart analyses by fluorescence in situ hybridization were simultaneously performed as a gold standard biomarker for synovial sarcoma. Five cases that were positive for the SS18 break-apart by fluorescence in situ hybridization were also positive for TLE1 by IHC, whereas the remaining 37 cases negative for SS18 break-apart were all negative for TLE1. The results showed no evidence of nonspecific TLE1 expression in the nonsynovial high-grade sarcomas. We concluded that TLE1 is a highly specific biomarker for synovial sarcoma in the setting of differential diagnosis of unclassified high-grade sarcomas.

Li W, Chu Y, Zhang L, et al.
Ginsenoside Rg1 attenuates tau phosphorylation in SK-N-SH induced by Aβ-stimulated THP-1 supernatant and the involvement of p38 pathway activation.
Life Sci. 2012; 91(15-16):809-15 [PubMed] Related Publications
AIM: In the present study we aimed to investigate the neuroprotective effect of ginsenoside Rg1 (GRg1) on neuronal damage examined in an adopted in vitro inflammatory neurodegeneration model and the involvement of p38 MAPK signal pathway.
MAIN METHODS: The supernatant from Aβ(1-40)-stimulated THP-1 monocytes was used as culture medium for SK-N-SH neuroblastoma cells which was used as target neuronal cells. The cell viability of SK-N-SH cells was assessed by detecting lactate dehydrogenase (LDH) leakage; the content of pro-inflammatory cytokine was measured by radioimmunoassay; the expressions of tau phosphorylation, p-38 and synaptophysin (SYN) were evaluated by western blot assay. The microtubule associated protein-2 (MAP-2) expression was confirmed by immunostaining.
KEY FINDINGS: Our results showed that incubation of the supernatant from Aβ(1-40)-stimulated THP-1 cells with SK-N-SH neuroblastoma cells for 24h significantly increased LDH leakage, tau and p-38 phosphorylation in SK-N-SH cells with increased interleukin (IL)-1β release into the supernatant of THP-1 cells. Pretreatment of THP-1 cells with GRg1 (50, 100 and 150μM) for 30min before Aβ(1-40)-stimulation inhibited THP-1 cell-mediated Aβ neurotoxicity towards SK-N-SH neuroblastoma and also decreased IL-1β release into THP-1 supernatant dose-dependently. An inhibitor of p38 MAPK, SB203580, had the same effect.
SIGNIFICANCE: These results suggested that activation of the p38 cell signal pathway may be involved in monocyte-mediated Aβ neurotoxicity towards SK-N-SH cells. Data obtained from this study demonstrated that GRg1 represented a potential treatment strategy for Alzheimer's disease (AD).

Jones KB, Su L, Jin H, et al.
SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas.
Oncogene. 2013; 32(18):2365-71, 2375.e1-5 [PubMed] Article available free on PMC after 12/12/2015 Related Publications
Synovial sarcoma is a deadly malignancy with limited sensitivity to traditional cytotoxic chemotherapy. SS18-SSX fusion oncogene expression characterizes human synovial sarcomas and drives oncogenesis in a mouse model. Elevated expression of BCL2 is considered a consistent feature of the synovial sarcoma expression profile. Our objective was to evaluate the expression of apoptotic pathway members in synovial sarcomas and interrogate the impact of modulating SS18-SSX expression on this pathway. We show in human and murine synovial sarcoma cells that SS18-SSX increases BCL2 expression, but represses other anti-apoptotic genes, including MCL1 and BCL2A1. This repression is achieved by directly suppressing expression via binding through activating transcription factor 2 (ATF2) to the cyclic adenosine monophosphate (AMP) response element (CRE) in the promoters of these genes and recruiting TLE1/Groucho. The suppression of these two anti-apoptotic pathways silences the typical routes by which other tumors evade BH3-domain peptidomimetic pharmacotherapy. We show that mouse and human synovial sarcoma cells are sensitive in vitro to ABT-263, a BH3-peptidomimetic, much more than the other tested cancer cell lines. ABT-263 also enhances the sensitivity of these cells to doxorubicin, a traditional cytotoxic chemotherapy used for synovial sarcoma. We also demonstrate the capacity of ABT-263 to stunt synovial sarcomagenesis in vivo in a genetic mouse model. These data recommend pursuit of BH3-peptidomimetic pharmacotherapy in human synovial sarcomas.

Su L, Sampaio AV, Jones KB, et al.
Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics.
Cancer Cell. 2012; 21(3):333-47 [PubMed] Article available free on PMC after 12/12/2015 Related Publications
Synovial sarcoma is a translocation-associated sarcoma where the underlying chromosomal event generates SS18-SSX fusion transcripts. In vitro and in vivo studies have shown that the SS18-SSX fusion oncoprotein is both necessary and sufficient to support tumorigenesis; however, its mechanism of action remains poorly defined. We have purified a core SS18-SSX complex and discovered that SS18-SSX serves as a bridge between activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1), resulting in repression of ATF2 target genes. Disruption of these components by siRNA knockdown or treatment with HDAC inhibitors rescues target gene expression, leading to growth suppression and apoptosis. Together, these studies define a fundamental role for aberrant ATF2 transcriptional dysregulation in the etiology of synovial sarcoma.

Knösel T, Chen Y, Hotovy S, et al.
Loss of desmocollin 1-3 and homeobox genes PITX1 and CDX2 are associated with tumor progression and survival in colorectal carcinoma.
Int J Colorectal Dis. 2012; 27(11):1391-9 [PubMed] Related Publications
BACKGROUND: Genomewide expression profiling has identified a number of genes differentially expressed in colorectal carcinomas (CRCs) compared to normal tissue. Some of these genes were linked to epithelial-mesenchymal transition. We tested whether genes including desmocollins and homeobox genes were distinct on the protein level and correlated the expression with clinicopathological data.
METHODS: Tissue microarrays of 402 R0-resected colorectal carcinomas of UICC stage II or III were constructed to evaluate ten biomarkers. Furthermore, mRNA expression of desmocollins was evaluated in eight colon cancer cell lines. Demethylation test was performed by treatment with 5-aza-2´-deoxycytide in five colon cancer cell lines.
RESULTS: On protein level, high expression of desmocollin 1 (DSC1) was observed in 41.6%, DSC2 in 58.0%, DSC3 in 61.4%, E-cadherin in 71.4%, CDX2 in 58.0%, PITX1 in 55.0%, CDK4 in 0.2%, TLE1 in 1.3%, Factor H in 42.5%, and MDM2 in 0.2%. Reduced expression of DSC1-3 was statistically linked to higher grading and DSC2, E-cadherin and CDX2 with shorter survival in high-grade carcinomas. Multivariate analysis showed that pathological stage and low PITX1 expression were statistically associated with shorter patients survival. On mRNA level, seven out of eight cell lines exhibited no expression of DSC1, and four out of seven restored DSC1 expression after demethylation test.
CONCLUSIONS: Reduced expression of PITX1 was independently correlated to shorter patients survival and could serve as a prognostic marker. Decreased expression of DSC1-3 is significantly correlated with higher tumor grading. Downregulation of DSC1 could be explained by DNA hypermethylation in colon cancer cells.

Villaroel-Salinas J, Campos-Martinez J, Ortiz-Hidalgo C
Synovial sarcoma of the tongue confirmed by molecular detection of the SYT-SSX2 fusion gene transcript.
Int J Surg Pathol. 2012; 20(4):386-9 [PubMed] Related Publications
Involvement of the tongue by a synovial sarcoma (SS) is an extremely rare event; there have only been 13 cases previously reported. The authors present herein a case of monophasic SS arising in the tongue in a 32-year-old woman. The neoplasm expressed cytokeratins AE1-3, OSCAR, and EMA as well as Bcl-2 and TLE1. Molecular analysis indicated that the patient tested positive for the SYT/SS2 fusion transcript.

Foo WC, Cruise MW, Wick MR, Hornick JL
Immunohistochemical staining for TLE1 distinguishes synovial sarcoma from histologic mimics.
Am J Clin Pathol. 2011; 135(6):839-44 [PubMed] Related Publications
Transducer-like enhancer of split 1 (TLE1) is overexpressed in synovial sarcomas. We investigated TLE1 expression by immunohistochemical analysis in a well-characterized series of synovial sarcomas and other mesenchymal tumors most commonly considered in the differential diagnosis. Whole tissue sections of 212 tumors were evaluated: 73 synovial sarcomas (23 biphasic, 28 monophasic, 22 poorly differentiated), 47 malignant peripheral nerve sheath tumors (MPNSTs), 49 solitary fibrous tumors (SFTs), 20 fibrosarcomatous variants of dermatofibrosarcoma protuberans, and 23 Ewing sarcomas/primitive neuroectodermal tumors (PNETs). All monophasic and poorly differentiated SSs and Ewing sarcoma/PNETs were previously confirmed to harbor t(X;18) and EWSR1 gene rearrangements, respectively. In total, 60 (82%) of 73 synovial sarcomas were positive for TLE1, including 18 biphasic (78%), 22 monophasic (79%), and 20 poorly differentiated (91%) tumors. Of the other tumors, only 7 MPNSTs (15%) and 4 SFTs (8%) were positive for TLE1, most of which showed only weak staining. TLE1 is a sensitive and specific marker for synovial sarcoma and can be helpful to distinguish synovial sarcoma from histologic mimics, particularly if moderate or strong staining is observed. In this study, only a small subset of MPNSTs and SFTs showed limited staining for TLE1.

Holmes KA, Hurtado A, Brown GD, et al.
Transducin-like enhancer protein 1 mediates estrogen receptor binding and transcriptional activity in breast cancer cells.
Proc Natl Acad Sci U S A. 2012; 109(8):2748-53 [PubMed] Article available free on PMC after 12/12/2015 Related Publications
Estrogen receptor (ER) binds to distal enhancers within the genome and requires additional factors, such as the Forkhead protein FoxA1, for mediating chromatin interactions. We now show that the human Groucho protein, Transducin-like enhancer protein 1 (TLE1), positively assists some ER-chromatin interactions, a role that is distinct from its general role as a transcriptional repressor. We show that specific silencing of TLE1 inhibits the ability of ER to bind to a subset of ER binding sites within the genome, a phenomenon that results in perturbations in phospho-RNA Pol II recruitment. Furthermore, TLE1 is essential for effective ER-mediated cell division. We have discovered a distinct role for TLE1, as a necessary transcriptional component of the ER complex, where it facilitates ER-chromatin interactions.

Geiersbach K, Rector LS, Sederberg M, et al.
Unknown partner for USP6 and unusual SS18 rearrangement detected by fluorescence in situ hybridization in a solid aneurysmal bone cyst.
Cancer Genet. 2011; 204(4):195-202 [PubMed] Related Publications
USP6 rearrangement is the most common genetic abnormality in primary aneurysmal bone cyst, and SS18 rearrangement has not been previously described in any type of tumor where synovial sarcoma was excluded from the differential diagnosis. We report a case of solid aneurysmal bone cyst in which fluorescence in situ hybridization (FISH) analysis indicated rearrangements of both USP6 and SS18, but histologic features were consistent with aneurysmal bone cyst throughout the lesion. Reverse-transcription polymerase chain reaction (RT-PCR) for the SS18-SSX1 and SS18-SSX2 translocations, identity testing, and SS18 FISH were performed on cytogenetic monolayer cultures and formalin-fixed paraffin-embedded (FFPE) tissue. Genomic microarray, FISH, and immunohistochemistry were performed on follow-up studies of the FFPE specimen. The karyotype was 45,X,add(X)(p11.2),add(4)(q13),add(8)(p21),-13,add(17)(p11.2),add(18)(q11.2) in all 20 cells analyzed from monolayer cultures. The karyotype showed no cytogenetically visible alterations of chromosomal regions harboring known partners for USP6. Metaphase FISH with a commercial SS18 break-apart probe showed translocation of the 5' portion of the SS18 probe to the short arm of the derivative X, as is observed in synovial sarcoma. RT-PCR showed no evidence of a SS18-SSX fusion, and immunohistochemistry was negative for TLE1, EMA, and cytokeratin AE1/3 expression. FISH on FFPE sections with a custom break-apart probe flanking USP6 showed evidence for a USP6 rearrangement throughout the tumor (25-50%). FISH on FFPE sections with a commercial SS18 break-apart FISH probe showed more variable results (0-50% split signals). There was no evidence of a SS18-USP6 fusion by FISH or RT-PCR. A molecular inversion probe array revealed a deletion encompassing the entire SS18 gene and its promoter, as well as portions of the region targeted by the commercial SS18 FISH probe. In conclusion, results obtained from commercially available FISH probes may occasionally yield misleading results. In this case, the SS18 rearrangement by FISH resulted from a complex rearrangement of 18q11.2 with a deletion of the SS18 gene. The translocation partner for USP6 remains unknown in this case.

Sameshima N, Marutsuka K, Tsukino H, et al.
So-called 'adenosarcoma' of the kidney a novel adult renal tumor with a cystic appearance.
Pathol Int. 2011; 61(5):313-8 [PubMed] Related Publications
We describe a novel cystic renal tumor consisting of benign epithelial and malignant stromal components in a 56-year-old woman who was admitted to hospital with macroscopic hematuria. Enhanced computed tomography revealed a multilocular 3.4 × 2.7-cm tumor in the center of the left kidney. After total left nephrectomy, the excised tumor appeared extensively cystic with a well defined border on the cut surface. Histologically, the tumor was composed of biphasic a benign epithelial lining on tubules or cysts with a typically hobnailed appearance, and anaplastic sarcomatous stroma with frequent mitosis. Periepithelial cuffing of the sarcoma cells was evident without an epithelial-stromal transition. Carcinomatous nests, blastemic elements, ovarian-like stroma or differentiated mesenchyme were not evident in the stroma. The epithelial cells were reactive with cytokeratins, epithelial membrane antigen (EMA), vimentin and transducin-like enhancer protein 1 (TLE1). Stromal cells were reactive with vimentin, CD99 and TLE1, partly reactive with CD34 and CD10, and non-reactive with cytokeratins, EMA, Wilm's tumor protein (WT-1), estrogen receptor (ER), progesterone receptor (PgR), CD57, HMB45 or Bcl2. SYT-SSX fusion gene was not detected with reverse transcription polymerase chain reaction. Because these findings did not coincide with established descriptions of cystic renal neoplasms, we preferred the term, 'adenosarcoma'. This could become a new classification for adult cystic renal tumors.

Seo SW, Lee H, Lee HI, Kim HS
The role of TLE1 in synovial sarcoma.
J Orthop Res. 2011; 29(7):1131-6 [PubMed] Related Publications
The treatment outcome of synovial sarcoma is poor owing to its resistance to radiation and chemotherapy. The transducin-like enhancer of split 1 (TLE1) is a co-repressor that involves many signaling pathways like cell survival, hematopoiesis and differentiation. Although TLE1 is uniquely expressed in synovial sarcomas, the biological role of TLE1 is not completely understood. This study evaluated the function of TLE1 in synovial sarcomas using knock-down of TLE1, and examined whether the inhibition of TLE1 suppresses the proliferation of synovial sarcomas and enhances the cytotoxicity caused by doxorubicin (doxo). The over-expression of TLE1 was first confirmed in synovial sarcoma cells (HS-SYII). When the HS-SYII cells and normal fibroblast were transiently transfected with TLE1 siRNA, the MTT assay revealed growth inhibition in the HS-SY-11 cells but not in the normal fibroblast. TLE1 silencing also potentiated the cytotoxic effects of doxo against HS-SYII cells. This effect of TLE1 silencing was attributed mainly to the induction of apoptosis. Subsequent analysis revealed that Bcl-2 is a possible downstream target of TLE1 signaling. This study demonstrated that TLE1 is a critical factor for the survival of synovial sarcomas. Overall, the inhibition of TLE1 affects cell proliferation and the apoptosis pathway by suppressing the expression of Bcl-2.

Sonoshita M, Aoki M, Fuwa H, et al.
Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling.
Cancer Cell. 2011; 19(1):125-37 [PubMed] Related Publications
Metastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in Apc(Δ716) intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis.

Nielsen TO
Discovery research to clinical trial: a ten year journey.
Clin Invest Med. 2010; 33(6):E342-8 [PubMed] Related Publications
Clinician-scientists have the training and motivation to translate basic science into tools for improved clinical care, but the road to achieve this is hardly straight forward, particularly for large scale genomic datasets. This year's Joe Doupe Young Investigator award winner, Dr. Torsten Nielsen, details successful examples of new scientific insights, diagnostics and clinical trials that have resulted from microarray-based gene expression profiling of sarcomas: TLE1 as a biomarker for synovial sarcoma, histone deacetylase inhibitor therapy for translocation-associated sarcomas of young adults, and CSF1 pathway inhibitors for tenosynovial giant cell tumors. Results from exciting, emerging next generation sequencing technologies will need to undergo similar validation and preclinical studies before they can be expected to impact patient care.

Di Masi A, Viganotti M, Antoccia A, et al.
Characterization of HuH6, Hep3B, HepG2 and HLE liver cancer cell lines by WNT/β - catenin pathway, microRNA expression and protein expression profile.
Cell Mol Biol (Noisy-le-grand). 2010; 56 Suppl:OL1299-317 [PubMed] Related Publications
Somatic mutations in the genes members of WNT/β-catenin pathway, especially in CTNNB1 codifying for β-catenin, have been found to play an important role in hepatocarcinogenesis. The purpose of this work is to characterize alterations of the WNT/β-catenin signalling pathway, and to study the expression pattern of a panel of microRNAs and proteins potentially involved in the pathogenesis of liver cancer. In this respect, the molecular characterization of the most used liver cancer cell lines HuH6, Hep3B, HepG2, and HLE, could represent a useful tool to identify novel molecular markers for hepatic tumour. A significant modulation of FZD7, NLK, RHOU, SOX17, TCF7L2, TLE1, SLC9A3R1 and WNT10A transcripts was observed in all the four liver cancer cell lines. The analysis of selected microRNAs showed that miR-122a, miR-125a and miR-150 could be suitable candidates to discriminate tumoural versus normal human primary hepatocytes. Finally, Grb-2 protein expression resulted to be increased more than two-fold in liver cancer cell lines in comparison to normal human primary hepatocytes. These advances in the knowledge of molecular mechanisms involved in the pathogenesis of liver cancer may provide new potential biomarkers and molecular targets for the diagnosis and therapy.

Bahrami A, Folpe AL
Adult-type fibrosarcoma: A reevaluation of 163 putative cases diagnosed at a single institution over a 48-year period.
Am J Surg Pathol. 2010; 34(10):1504-13 [PubMed] Related Publications
Adult-type fibrosarcoma (FS) was once considered the most common adult sarcoma, but is now considered a diagnosis of exclusion. No recent series has critically reevaluated putative FSs to estimate their true incidence. One hundred ninety-five cases diagnosed as adult FS in somatic soft tissue were retrieved from our institutional archives for the period 1960 to 2008. Thirty-two cases with insufficient material were excluded. On the basis the morphology of the final 163 cases, immunohistochemical studies (IHC) was conducted using some combination of: wide-spectrum cytokeratin (CK), EMA, high molecular weight CK, S100, Melan A, HMB-45, CD34, TLE1, CD31, HHV8, smooth muscle actin, desmin, ALK1, CD99, Myo-D1, myogenin, c-kit, INI1, CD21, p63, calretinin, WT1, and TTF1. Fluorescence in situ hybridization analysis for SYT gene rearrangement was done in 6 putative CK-negative synovial sarcomas (SS). Revised diagnoses were based on clinical, morphologic, IHC, and molecular findings. The original group of putative FS occurred in 84 males and 79 females (median 52.5 y, range 2 to 99 y), and involved various anatomic sites. Only 26 cases met WHO criteria for FS, including 2 postradiation FS. These occurred in 16 males and 10 females (median 50 y, range 6 to 74 y), and involved the lower extremities (12 cases), head/ neck (5 cases), trunk (4 cases), upper extremities (3 case), and mediastinum/abdomen (2 cases). Clinical follow-up information was available for 24 of 26 (92%) cases, with a median of 5 years follow-up (range <1 to 35 y). Twelve patients (50%) died of locally aggressive and/or metastatic disease (median follow-up 1-year; range <1 to 8 y), 6 patients (25%) were alive without disease (median follow-up 11.5 y; range 2.5 to 35 y), and 6 patients (25%) died of other causes (median follow-up 10 y; range 9 to 18 y) (). Fluorescence in situ hybridization analysis was positive for SYT gene rearrangement in all cases tested. Non-FS (137 cases) were reclassified as: undifferentiated pleomorphic sarcoma (32 cases), SS (21 cases), solitary fibrous tumor (14 cases), myxofibrosarcoma (11 cases), malignant peripheral nerve sheath tumor (8 cases), FS dermatofibrosarcoma protuberans, and desmoplastic melanoma (4 cases each), low-grade fibromyxoid sarcoma, sarcomatoid carcinoma, desmoid-type fibromatosis, rhabdomyosarcoma, myofibroblastic sarcoma, spindle-cell liposarcoma (3 cases each), sclerosing epithelioid FS, fibroma-like epithelioid sarcoma, leiomyosarcoma, cellular fibrous histiocytoma (2 cases each), and others (17 cases). Using modern diagnostic criteria with ancillary IHC and molecular genetics, we have been able to reclassify 84% of putative FS. Exclusive of undifferentiated pleomorphic sarcoma, the distinction of which from FS is subjective, 64% of putative FS were reclassified, most commonly as monophasic SS and solitary fibrous tumor. We conclude that true FS is exceedingly rare, accounting for <1% of approximately 10,000 adult soft tissue sarcomas seen at our institution during this time period, and should be diagnosed with great caution.

Knösel T, Heretsch S, Altendorf-Hofmann A, et al.
TLE1 is a robust diagnostic biomarker for synovial sarcomas and correlates with t(X;18): analysis of 319 cases.
Eur J Cancer. 2010; 46(6):1170-6 [PubMed] Related Publications
INTRODUCTION: Genomewide expression profiling has identified a number of genes expressed at higher levels in synovial sarcoma than in other sarcomas. Our objectives in this study were (1) to test whether the differentially expressed gene, Transducin-Like Enhancer of split (TLE1) belonging to the groucho/TLE family, is also distinct on the protein level; (2) to evaluate this biomarker in a series of well-characterised synovial sarcomas on standard, full-sized tissue sections and (3) to correlate the expression of TLE1 with t(X;18) and other established biomarkers.
METHODS: Three-hundred and eighty four spindle cell sarcomas from the German consultation and reference centre of soft tissue tumours initially suspected for synovial sarcoma were revisited. Three-hundred and nineteen of these specimens were analysed immunohistochemically using a monoclonal antibody TLE1 and standard, full-sized tissue sections. The nuclear staining was scored semiquantitatively as -, negative; +, weak; ++, moderate and +++, strong positive. Furthermore, 118 specimens among these were further analysed using FISH and/or PCR to detect t(X;18). We correlated the TLE1 expression with the t(X;18) translocation and other established biomarkers (EMA, PanCK, CK7, CD34 and BCL2).
RESULTS: TLE1 expression was observed in 96% of the synovial sarcomas (score+, 249/259) and discriminates them from other soft tissue tumours (p<0.001). Multivariate analysis showed that positive TLE1 staining was a statistically independent diagnostic marker. Furthermore molecular analysis showed that t(X;18) was clearly correlated with TLE1 protein expression (p<0.001).
CONCLUSIONS: Expression of TLE1 is significantly correlated with t(X;18) and may serve as a new robust diagnostic biomarker in synovial sarcomas and potential therapeutic target.

Noy P, Williams H, Sawasdichai A, et al.
PRH/Hhex controls cell survival through coordinate transcriptional regulation of vascular endothelial growth factor signaling.
Mol Cell Biol. 2010; 30(9):2120-34 [PubMed] Article available free on PMC after 12/12/2015 Related Publications
The proline-rich homeodomain protein (PRH) plays multiple roles in the control of gene expression during embryonic development and in the adult. Vascular endothelial growth factor (VEGF) is a mitogen that stimulates cell proliferation and survival via cell surface receptors including VEGFR-1 and VEGFR-2. VEGF signaling is of critical importance in angiogenesis and hematopoiesis and is elevated in many tumors. Here we show that PRH binds directly to the promoter regions of the Vegf, Vegfr-1, and Vegfr-2 genes and that in each case PRH represses transcription. We demonstrate that overexpression or knockdown of PRH directly impinges on the survival of both leukemic and tumor cells and that the modulation of VEGF and VEGF receptor signaling by PRH mediates these effects. Our findings demonstrate that PRH is a key regulator of the VEGF signaling pathway and describe a mechanism whereby PRH plays an important role in tumorigenesis and leukemogenesis.

Nagel S, Venturini L, Przybylski GK, et al.
NK-like homeodomain proteins activate NOTCH3-signaling in leukemic T-cells.
BMC Cancer. 2009; 9:371 [PubMed] Article available free on PMC after 12/12/2015 Related Publications
BACKGROUND: Homeodomain proteins control fundamental cellular processes in development and in cancer if deregulated. Three members of the NK-like subfamily of homeobox genes (NKLs), TLX1, TLX3 and NKX2-5, are implicated in T-cell acute lymphoblastic leukemia (T-ALL). They are activated by particular chromosomal aberrations. However, their precise function in leukemogenesis is still unclear. Here we screened further NKLs in 24 T-ALL cell lines and identified the common expression of MSX2. The subsequent aim of this study was to analyze the role of MSX2 in T-cell differentiation which may be disturbed by oncogenic NKLs.
METHODS: Specific gene activity was examined by quantitative real-time PCR, and globally by expression profiling. Proteins were analyzed by western blot, immuno-cytology and immuno-precipitation. For overexpression studies cell lines were transduced by lentiviruses.
RESULTS: Quantification of MSX2 mRNA in primary hematopoietic cells demonstrated higher levels in CD34+ stem cells as compared to peripheral blood cells and mature CD3+ T-cells. Furthermore, analysis of MSX2 expression levels in T-cell lines after treatment with core thymic factors confirmed their involvement in regulation. These results indicated that MSX2 represents an hematopoietic NKL family member which is downregulated during T-cell development and may functionally substituted by oncogenic NKLs. For functional analysis JURKAT cells were lentivirally transduced, overexpressing either MSX2 or oncogenic TLX1 and NKX2-5, respectively. These cells displayed transcriptional activation of NOTCH3-signaling, including NOTCH3 and HEY1 as analyzed by gene expression profiling and quantitative RT-PCR, and consistently attenuated sensitivity to gamma-secretase inhibitor as analyzed by MTT-assays. Furthermore, in addition to MSX2, both TLX1 and NKX2-5 proteins interacted with NOTCH-pathway repressors, SPEN/MINT/SHARP and TLE1/GRG1, representing a potential mechanism for (de)regulation. Finally, elevated expression of NOTCH3 and HEY1 was detected in primary TLX1/3 positive T-ALL cells corresponding to the cell line data.
CONCLUSION: Identification and analysis of MSX2 in hematopoietic cells implicates a modulatory role via NOTCH3-signaling in early T-cell differentiation. Our data suggest that reduction of NOTCH3-signaling by physiological downregulation of MSX2 expression during T-cell development is abrogated by ectopic expression of oncogenic NKLs, substituting MSX2 function.

Jagdis A, Rubin BP, Tubbs RR, et al.
Prospective evaluation of TLE1 as a diagnostic immunohistochemical marker in synovial sarcoma.
Am J Surg Pathol. 2009; 33(12):1743-51 [PubMed] Related Publications
Synovial sarcoma is a high-grade soft tissue sarcoma that can be challenging to diagnose on the basis of histology alone. It is defined by a characteristic translocation t(X;18) that produces the fusion oncogene SYT-SSX. The current diagnostic gold standard for synovial sarcoma is the demonstration of the translocation by fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, or cytogenetics, in an appropriate histologic context. TLE1 encodes a transcriptional corepressor that is overexpressed in synovial sarcomas. Gene and tissue microarray studies have identified TLE1 as an excellent bio-marker for distinguishing the synovial sarcoma from other soft tissue malignancies. We prospectively evaluated incoming soft tissue tumor cases where the histology and clinical setting made synovial sarcoma a real consideration in the differential diagnosis. TLE1, Bcl2, epithelial membrane antigen, and cytokeratin expression were assessed using commercially available antibodies. TLE1 gave intense, diffuse nuclear staining in 35 of 35 molecularly confirmed synovial sarcoma cases, and was rare to absent in the 73 other soft tissue tumors examined (positive staining was found only in 1 of 43 malignant peripheral nerve sheath tumors, the 1 tested fibrosarcoma, and 1 pleomorphic sarcoma). TLE1 was more sensitive and specific for synovial sarcoma than other currently available immunohistochemical markers including Bcl2, epithelial membrane antigen and cytokeratins, and had a positive predictive value of 92% and a negative predictive value of 100% in this clinical setting. Our findings confirm, in a prospective diagnostic context, that TLE1 is more sensitive and specific for synovial sarcoma than any other currently available immunohistochemical stains, and in some cases may preclude the need for molecular testing.

Lovisa F, Mussolin L, Corral L, et al.
IGH and IGK gene rearrangements as PCR targets for pediatric Burkitt's lymphoma and mature B-ALL MRD analysis.
Lab Invest. 2009; 89(10):1182-6 [PubMed] Related Publications
We recently reported that minimal residual disease (MRD) and minimal disseminated disease (MDD), assessed by long-distance PCR (LD-PCR) for t(8;14), are negative prognostic factors in mature B-cell acute lymphoblastic leukemia (B-ALL) and in Burkitt's lymphoma (BL). However, t(8;14) is detectable in only about 70% of patients, thus preventing MRD studies by this approach in the remaining patients. At present, no molecular assays have been reported for MRD and MDD analysis in t(8;14)-negative patients. The aim of our study was to evaluate the characteristics of patient-specific immunoglobulin (Ig) gene rearrangements as RQ-PCR targets for MRD analysis, in order to extend MRD studies to those patients who are not eligible for the LD-PCR assay. The study was performed according to the guidelines of the European Study Group on MRD detection in ALL (ESG-MRD-ALL). Overall, 36 B-ALL and 19 BL cases were analyzed. Multiple PCR reactions were performed for each sample to identify heavy and kappa light-chain rearrangements. A total of 97 RQ-PCR targets (62 for B-ALL, 35 for BL) were analyzed for sensitivity. The rearrangement pattern identified was similar to that reported for normal peripheral blood lymphocytes. In 88% of the targets, a sensitivity of at least 10(-4) was achieved. In 87% of patients (84% of B-ALLs, 95% of BLs) at least one sensitive target was available. All PCR targets identified at diagnosis were preserved at relapse. Our results suggest that MDD and MRD can be successfully studied using a single sensitive Ig target in the great majority of B-ALL and BL cases. The combination of LD-PCR and Ig-based assays will allow MRD analysis in virtually all of the patients.

Folpe AL, Lloyd RV, Bacchi CE, Rosai J
Spindle epithelial tumor with thymus-like differentiation: a morphologic, immunohistochemical, and molecular genetic study of 11 cases.
Am J Surg Pathol. 2009; 33(8):1179-86 [PubMed] Related Publications
Spindle epithelial tumor with thymus-like differentiation (SETTLE) is an extremely rare tumor of the thyroid and neck, first described by Chan and Rosai. SETTLE is a low-grade malignancy, with potential for late lung, lymph node, and other visceral metastases. The clinicopathologic features of SETTLE overlap significantly with those of synovial sarcoma. Thirteen cases previously diagnosed as "SETTLE" (11 cases) or "malignant neoplasm-SETTLE versus synovial sarcoma" (2 cases), were retrieved. Immunohistochemistry for low-molecular-weight cytokeratins, high-molecular-weight cytokeratins, cytokeratin 7, cytokeratin 20, epithelial membrane antigen, bcl-2, CD34, CD99, CD117, INI-1, and TLE1 were performed. Reverse transcriptase polymerase chain reaction for the SS18/SSX1 and SS18/SSX2 fusion genes and fluorescent in-situ hybridization for SYT rearrangement was performed. The 11 cases diagnosed, as "SETTLE" were negative for synovial sarcoma-associated fusion genes, whereas the other 2 cases were positive. SETTLE occurred in 7 females and 4 males (7 to 50 y of age, median 13.5 y) and involved the thyroid gland in 10 cases. Clinical follow-up showed 3 patients to be disease-free 7, 10, and 15 years after surgery. One patient had a lymph node metastasis at diagnosis and lung metastases 14 months after diagnosis. SETTLE infiltrated the thyroid, and consisted of a vaguely nodular admixture of fascicular, reticular, hyalinized, and microcystic areas. Spindled zones blended imperceptibly into areas showing epithelial differentiation, in the form of glomeruloid glandular structures, sertoli-like tubules, and small glands, lined by cuboidal to columnar cells. Mitotic activity was very low, necrosis was absent, and pleomorphism was not present. By immunohistochemistry, SETTLE showed extensive expression of high-molecular-weight cytokeratins in 7 of 8 cases (88%). Expression of low-molecular-weight cytokeratins and epithelial membrane antigen was limited, confined to only scattered cells in 7 of 8 (88%), and 4 of 8 (50%) of cases, respectively. Cytokeratin 7 expression was more widespread (7 of 8 cases, 88%). Cytokeratin 20 was negative. Expression of CD99 and bcl-2 was seen in 6 of 8 (75%) and 7 of 8 (88%) cases, respectively. CD117, INI-1, and TLE1 expression was seen in 6 of 8 (75%), 8 of 8 (100%), and 1 of 5 (20%) of cases, respectively. We conclude that traditional morphologic study and a limited panel of ancillary immunostains are sufficient for the distinction of SETTLE from synovial sarcoma in almost all instances. Molecular genetic study may, however, be helpful in selected cases, particularly in limited biopsies.

Kosemehmetoglu K, Vrana JA, Folpe AL
TLE1 expression is not specific for synovial sarcoma: a whole section study of 163 soft tissue and bone neoplasms.
Mod Pathol. 2009; 22(7):872-8 [PubMed] Related Publications
TLE1, a transcriptional repressor essential in hematopoiesis, neuronal differentiation and terminal epithelial differentiation, has recently been shown in a single tissue microarray study to be a highly sensitive and relatively specific marker of synovial sarcomas. Expression of TLE1 has not, however, been studied in standard sections of soft tissue and bone tumors. We investigated TLE1 expression in a large series of well-characterized mesenchymal tumors, to more fully characterize the range of TLE1 expression. Standard sections of 163 bone and soft tissue tumors were immunostained for TLE1 (sc-9121, 1:100; Santa Cruz Biochemicals) using the Dako Dual Envision+ detection system. Nuclear positivity was scored as negative (<5% of cell positive), 1+ (5-25% of cells positive), 2+ (25-50% of cells positive), and 3+ (>50% of cells positive). Overall, TLE1 was expressed by 18 of 20 (90%) of synovial sarcoma, with 16 cases (89%) showing 2-3+ positivity. However, TLE1 expression was also seen in 53 of 143 (37%) non-synovial sarcoma, with 36 such cases (25%) showing 2-3+ positivity. TLE1 expression was commonly seen in peripheral nerve sheath tumors, including 33% of neurofibromas, 100% of schwannomas, and 30% of malignant peripheral nerve sheath tumors. Among non-neoplastic tissues, nuclear TLE1 expression was variably present in basal keratinocytes, adipocytes, perineurial cells, endothelial cells and mesothelial cells. Our study confirms the excellent sensitivity of TLE1 for synovial sarcoma. However, TLE1 expression is by no means specific for synovial sarcoma, being present in a number of tumors, which enter its differential diagnosis, in particular tumors of peripheral nerve sheath origin. Heterogeneity of TLE1 expression likely explains the differences between the present standard section study and the earlier TMA study. TLE1 may be of value in the differential diagnosis of synovial sarcoma, but should be used only in the context of a panel of antibodies. Morphology, ancillary immunohistochemistry for traditional markers such as cytokeratins and CD34, and molecular confirmation of synovial sarcoma-associated fusion genes should remain the 'gold standards' for this diagnosis.

Mrózek K, Marcucci G, Paschka P, Bloomfield CD
Advances in molecular genetics and treatment of core-binding factor acute myeloid leukemia.
Curr Opin Oncol. 2008; 20(6):711-8 [PubMed] Article available free on PMC after 12/12/2015 Related Publications
PURPOSE OF REVIEW: Core-binding factor (CBF) acute myeloid leukemia (AML) is among the most common cytogenetic subtypes of AML, being detected in approximately 13% of adults with primary disease. Although CBF-AML is associated with a relatively favorable prognosis, only one-half of the patients are cured. Herein we review recent discoveries of genetic and epigenetic alterations in CBF-AML that may represent novel prognostic markers and therapeutic targets and lead to improvement of the still disappointing clinical outcome of these patients.
RECENT FINDINGS: Several acquired gene mutations and gene-expression and microRNA-expression changes that occur in addition to t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22), the cytogenetic hallmarks of CBF-AML, have been recently reported. Alterations that may represent cooperative events in CBF-AML leukemogenesis include mutations in the KIT, FLT3, JAK2 and RAS genes, haploinsufficiency of the putative tumor suppressor genes TLE1 and TLE4 in t(8;21)-positive patients with del(9q), MN1 overexpression in inv(16) patients, and epigenetic and posttranscriptional silencing of CEBPA. Genome-wide gene-expression and microRNA-expression profiling identifying subgroups of CBF-AML patients with distinct molecular signatures, different clinical outcomes, or both, have also been reported.
SUMMARY: Progress has been made in delineating the genetic basis of CBF-AML that will likely result in improved prognostication and development of novel, risk-adapted therapeutic approaches.

Godman CA, Joshi R, Tierney BR, et al.
HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling.
Cancer Biol Ther. 2008; 7(10):1570-80 [PubMed] Article available free on PMC after 12/12/2015 Related Publications
Histone deacetylase 3 (HDAC3) is overexpressed in approximately half of all colon adenocarcinomas. We took an RNAi approach to determine how HDAC3 influenced chromatin modifications and the expression of growth regulatory genes in colon cancer cells. A survey of histone modifications revealed that HDAC3 knockdown in SW480 cells significantly increased histone H4-K12 acetylation, a modification present during chromatin assembly that has been implicated in imprinting. This modification was found to be most prominent in proliferating cells in the intestinal crypt and in APC(Min) tumors, but was less pronounced in the tumors that overexpress HDAC3. Gene expression profiling of SW480 revealed that HDAC3 shRNA impacted the expression of genes in the Wnt and vitamin D signaling pathways. The impact of HDAC3 on Wnt signaling was complex, with both positive and negative effects observed. However, long-term knockdown of HDAC3 suppressed beta-catenin translocation from the plasma membrane to the nucleus, and increased expression of Wnt inhibitors TLE1, TLE4 and SMO. HDAC3 knockdown also enhanced expression of the TLE1 and TLE4 repressors in HT-29 and HCT116 cells. HDAC3 shRNA enhanced expression of the vitamin D receptor in SW480 and HCT116 cells, and rendered SW480 cells sensitive to 1,25-dihydroxyvitamin D3. We propose that HDAC3 overexpression alters the epigenetic programming of colon cancer cells to impact intracellular Wnt signaling and their sensitivity to external growth regulation by vitamin D.

Sang L, Coller HA, Roberts JM
Control of the reversibility of cellular quiescence by the transcriptional repressor HES1.
Science. 2008; 321(5892):1095-100 [PubMed] Article available free on PMC after 12/12/2015 Related Publications
The mechanisms by which quiescent cells, including adult stem cells, preserve their ability to resume proliferation after weeks or even years of cell cycle arrest are not known. We report that reversibility is not a passive property of nondividing cells, because enforced cell cycle arrest for a period as brief as 4 days initiates spontaneous, premature, and irreversible senescence. Increased expression of the gene encoding the basic helix-loop-helix protein HES1 was required for quiescence to be reversible, because HES1 prevented both premature senescence and inappropriate differentiation in quiescent fibroblasts. In some human tumors, the HES1 pathway was activated, which allowed these cells to evade differentiation and irreversible cell cycle arrest. We conclude that HES1 safeguards against irreversible cell cycle exit both during normal cellular quiescence and pathologically in the setting of tumorigenesis.

Fraga MF, Berdasco M, Ballestar E, et al.
Epigenetic inactivation of the Groucho homologue gene TLE1 in hematologic malignancies.
Cancer Res. 2008; 68(11):4116-22 [PubMed] Related Publications
An undifferentiated status and the epigenetic inactivation of tumor-suppressor genes are hallmarks of transformed cells. Promoter CpG island hypermethylation of differentiating genes, however, has rarely been reported. The Groucho homologue Transducin-like Enhancer of Split 1 (TLE1) is a multitasked transcriptional corepressor that acts through the acute myelogenous leukemia 1, Wnt, and Notch signaling pathways. We have found that TLE1 undergoes promoter CpG island hypermethylation-associated inactivation in hematologic malignancies, such as diffuse large B-cell lymphoma and AML. We also observed a mutual exclusivity of the epigenetic alteration of TLE1 and the cytogenetic alteration of AML1. TLE1 reintroduction in hypermethylated leukemia/lymphoma cells causes growth inhibition in colony assays and nude mice, whereas TLE1-short hairpin RNA depletion in unmethylated cells enhances tumor growth. We also show that these effects are mediated by TLE1 transcriptional repressor activity on its target genes, such as Cyclin D1, Colony-Stimulating Factor 1 receptor, and Hairy/Enhancer of Split 1. These data suggest that TLE1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting critical differentiation and growth-suppressing pathways.

Nakaya HI, Beckedorff FC, Baldini ML, et al.
Splice variants of TLE family genes and up-regulation of a TLE3 isoform in prostate tumors.
Biochem Biophys Res Commun. 2007; 364(4):918-23 [PubMed] Related Publications
The TLE genes constitute a family of important transcriptional co-repressors involved in many cellular processes. We found evidence of alternatively spliced mRNAs for human TLE1-4 containing premature stop codons, thus encoding putative shortened proteins. Microarray experiments and Real-time RT-PCR assays showed that alternatively spliced isoforms of TLE1, TLE2 an d TLE3 were preferentially expressed in prostate in comparison to liver and kidney tissues. We identified by orientation-specific R T-PCR an antisense partially intronic non-coding RNA that overlaps a novel exon of the TLE3 gene, raising the possibility of regulation of alternative splicing by this non-coding transcript. The alternatively spliced isoform of TLE3 was up-regulated (6- to 17-fo ld) in prostate tumors in comparison to matched non-tumor adjacent tissue from 7 out of 11 (64%) patients and in four prostate tumor cell lines in comparison to a normal prostate cell line. These results demonstrate that different isoforms of TLE genes are commonly transcribed in human tissues and suggest that TLE3 could be involved in prostate cancer development.

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