TRIM33; tripartite motif containing 33 (1p13.1)

Gene Summary

Gene:TRIM33; tripartite motif containing 33
Summary:The protein encoded by this gene is thought to be a transcriptional corepressor. However, molecules that interact with this protein have not yet been identified. The protein is a member of the tripartite motif family. This motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. Three alternatively spliced transcript variants for this gene have been described, however, the full-length nature of one variant has not been determined. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:E3 ubiquitin-protein ligase TRIM33
Updated:14 December, 2014


What does this gene/protein do?
Show (19)

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 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.

  • Base Sequence
  • Promoter Regions
  • cabozantinib
  • Chromosome Breakage
  • Tumor Suppressor Proteins
  • TRIM29
  • Ubiquitination
  • Azacitidine
  • TP53
  • Leukemic Gene Expression Regulation
  • Genetic Recombination
  • Pyridines
  • Bone Marrow
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Hematopoietic Stem Cells
  • Lung Cancer
  • Hematopoiesis
  • Tumor Suppressor Gene
  • Chromosome 1
  • Chronic Myelomonocytic Leukemia
  • Adenocarcinoma
  • Transcription
  • Disease-Free Survival
  • Repressor Proteins
  • Neoplastic Cell Transformation
  • Transcription Factors
  • Non-Small Cell Lung Cancer
  • DNA Methylation
  • Ubiquitin-Protein Ligases
  • Repetitive Sequences, Nucleic Acid
  • Proto-Oncogene Proteins c-ret
  • Kras2 protein, mouse
  • Anilides
  • Neoplasm Proteins
  • Aging
  • Autoantigens
  • Cell Differentiation
  • Translocation
  • TRIM22
Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Related Links

Latest Publications: TRIM33 (cancer-related)

Beckenkamp A, Santana DB, Bruno AN, et al.
Ectonucleotidase expression profile and activity in human cervical cancer cell lines.
Biochem Cell Biol. 2014; 92(2):95-104 [PubMed] Related Publications
Cervical cancer is the third most frequent cancer in women worldwide. Adenine nucleotide signaling is modulated by the ectonucleotidases that act in sequence, forming an enzymatic cascade. Considering the relationship between the purinergic signaling and cancer, we studied the E-NTPDases, ecto-5'-nucleotidase, and E-NPPs in human cervical cancer cell lines and keratinocytes. We evaluated the expression profiles of these enzymes using RT-PCR and quantitative real-time PCR analysis. The activities of these enzymes were examined using ATP, ADP, AMP, and p-nitrophenyl-5'-thymidine monophosphate (p-Nph-5'-TMP) as substrate, in a colorimetric assay. The extracellular adenine nucleotide hydrolysis was estimated by HPLC analysis. The hydrolysis of all substrates exhibited a linear pattern and these activities were cation-dependent. An interesting difference in the degradation rate was observed between cervical cancer cell lines SiHa, HeLa, and C33A and normal imortalized keratinocytes, HaCaT cells. The mRNA of ecto-5'-nucleotidase, E-NTPDases 5 and 6 were detectable in all cell lines, and the dominant gene expressed was the Entpd 5 enzyme, in SiHa cell line (HPV16 positive). In accordance with this result, a higher hydrolysis activity for UDP and GDP nucleotides was observed in the supernatant of the SiHa cells. Both normal and cancer cells presented activity and mRNAs of members of the NPP family. Considering that these enzymes exert an important catalytic activity, controlling purinergic nucleotide concentrations in tumors, the presence of ectonucleotidases in cervical cancer cells can be important to regulate the levels of extracellular adenine nucleotides, limiting their effects.

Related: Cervical Cancer

Xue J, Lin X, Chiu WT, et al.
Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β-dependent cancer metastasis.
J Clin Invest. 2014; 124(2):564-79 [PubMed] Free Access to Full Article Related Publications
A key feature of TGF-β signaling activation in cancer cells is the sustained activation of SMAD complexes in the nucleus; however, the drivers of SMAD activation are poorly defined. Here, using human and mouse breast cancer cell lines, we found that oncogene forkhead box M1 (FOXM1) interacts with SMAD3 to sustain activation of the SMAD3/SMAD4 complex in the nucleus. FOXM1 prevented the E3 ubiquitin-protein ligase transcriptional intermediary factor 1 γ (TIF1γ) from binding SMAD3 and monoubiquitinating SMAD4, which stabilized the SMAD3/SMAD4 complex. Loss of FOXM1 abolished TGF-β-induced SMAD3/SMAD4 formation. Moreover, the interaction of FOXM1 and SMAD3 promoted TGF-β/SMAD3-mediated transcriptional activity and target gene expression. We found that FOXM1/SMAD3 interaction was required for TGF-β-induced breast cancer invasion, which was the result of SMAD3/SMAD4-dependent upregulation of the transcription factor SLUG. Importantly, the function of FOXM1 in TGF-β-induced invasion was not dependent on FOXM1's transcriptional activity. Knockdown of SMAD3 diminished FOXM1-induced metastasis. Furthermore, FOXM1 levels correlated with activated TGF-β signaling and metastasis in human breast cancer specimens. Together, our data indicate that FOXM1 promotes breast cancer metastasis by increasing nuclear retention of SMAD3 and identify crosstalk between FOXM1 and TGF-β/SMAD3 pathways. This study highlights the critical interaction of FOXM1 and SMAD3 for controlling TGF-β signaling during metastasis.

Related: Signal Transduction SMAD3 MADH4 FOXM1

Ko A, Kanehisa A, Martins I, et al.
Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling.
Cell Death Differ. 2014; 21(1):92-9 [PubMed] Free Access to Full Article Related Publications
Clinical oncology heavily relies on the use of radiotherapy, which often leads to merely transient responses that are followed by local or distant relapse. The molecular mechanisms explaining radioresistance are largely elusive. Here, we identified a dual role of autophagy in the response of cancer cells to ionizing radiation. On one hand, we observed that the depletion of essential autophagy-relevant gene products, such as ATG5 and Beclin 1, increased the sensitivity of human or mouse cancer cell lines to irradiation, both in vitro (where autophagy inhibition increased radiation-induced cell death and decreased clonogenic survival) and in vivo, after transplantation of the cell lines into immunodeficient mice (where autophagy inhibition potentiated the tumour growth-inhibitory effect of radiotherapy). On the other hand, when tumour proficient or deficient for autophagy were implanted in immunocompetent mice, it turned out that defective autophagy reduced the efficacy of radiotherapy. Indeed, radiotherapy elicited an anti-cancer immune response that was dependent on autophagy-induced ATP release from stressed or dying tumour cells and was characterized by dense lymphocyte infiltration of the tumour bed. Intratumoural injection of an ecto-ATPase inhibitor restored the immune infiltration of autophagy-deficient tumours post radiotherapy and improved the growth-inhibitory effect of ionizing irradiation. Altogether, our results reveal that beyond its cytoprotective function, autophagy confers immunogenic properties to tumours, hence amplifying the efficacy of radiotherapy in an immunocompetent context. This has far-reaching implications for the development of pharmacological radiosensitizers.

Related: Cancer Prevention and Risk Reduction

Allard B, Turcotte M, Spring K, et al.
Anti-CD73 therapy impairs tumor angiogenesis.
Int J Cancer. 2014; 134(6):1466-73 [PubMed] Related Publications
CD73 is an ecto-nucleotidase overexpressed in various types of tumors that catabolizes the generation of extracellular adenosine, a potent immunosuppressor. We and others have shown that targeted blockade of CD73 can rescue anti-tumor T cells from the immunosuppressive effects of extracellular adenosine. Another important function of extracellular adenosine is to regulate adaptive responses to hypoxia. However, the importance of CD73 for tumor angiogenesis and the effect of anti-CD73 therapy on tumor angiogenesis remain unknown. In this study, we demonstrated that CD73 expression on tumor cells and host cells contribute to tumor angiogenesis. Our data revealed that tumor-derived CD73 enhances the production of vascular endothelial growth factor (VEGF) by tumor cells that host-derived CD73 is required for in vivo angiogenic responses and that endothelial cells require CD73 expression for tube formation and migration. Notably, the pro-angiogeneic effects of CD73 relied on both enzymatic and non-enzymatic functions. Using a mouse model of breast cancer, we demonstrated that targeted blockade of CD73 with a monoclonal antibody significantly decreased tumor VEGF levels and suppressed tumor angiogenesis in vivo. Taken together, our study strongly suggests that targeted blockade of CD73 can significantly block tumor angiogenesis, and further supports its clinical development for cancer treatment.

Related: Monoclonal Antibodies Breast Cancer Angiogenesis and Cancer VEGFA

Wang JL, Tong CW, Chang WT, Huang AM
Novel genes FAM134C, C3orf10 and ENOX1 are regulated by NRF-1 and differentially regulate neurite outgrowth in neuroblastoma cells and hippocampal neurons.
Gene. 2013; 529(1):7-15 [PubMed] Related Publications
Nuclear respiratory factor-1 (NRF-1) is a major transcription factor in the human genome and functions in neurite outgrowth in neuroblastoma cells. Whether genes downstream from NRF-1 differentially regulate axonal and dendritic outgrowth in neurons remains largely unknown. Three hypothetical genes, C3orf10, FAM134C, and ENOX1, were investigated because their NRF-1 response elements are 100% conserved in humans and mice. We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. FAM134C but not C3orf10 mediates NRF-1-enhanced neurite outgrowth. In primary rat hippocampal neurons, Fam134c is predominantly expressed in the axon hillock and C3orf10 is ubiquitously expressed in all neurites and cell bodies at different developmental stages, suggesting their roles in axonal and dendritic outgrowth. Knockdown of Fam134c decreased both axonal length and the number of axonal collaterals and dendrites, however, knockdown of C3orf10 only increased the number of axonal collaterals and dendrites. Overall, we annotated FAM134C, C3orf10, and ENOX1 as NRF-1-regulated genes, which have differential effects on neurite outgrowth in neuroblastoma cells as well as neurons. This study provided an effective platform for annotating hypothetical genes in the human genome and increasing our knowledge in the molecular network underlying neuronal differentiation.

Related: Neuroblastoma

Garg AD, Dudek AM, Ferreira GB, et al.
ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death.
Autophagy. 2013; 9(9):1292-307 [PubMed] Related Publications
Calreticulin surface exposure (ecto-CALR), ATP secretion, maturation of dendritic cells (DCs) and stimulation of T cells are prerequisites for anticancer therapy-induced immunogenic cell death (ICD). Recent evidence suggests that chemotherapy-induced autophagy may positively regulate ICD by favoring ATP secretion. We have recently shown that reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress triggered by hypericin-mediated photodynamic therapy (Hyp-PDT) induces bona fide ICD. However, whether Hyp-PDT-induced autophagy regulates ICD was not explored. Here we showed that, in contrast to expectations, reducing autophagy (by ATG5 knockdown) in cancer cells did not alter ATP secretion after Hyp-PDT. Autophagy-attenuated cancer cells displayed enhanced ecto-CALR induction following Hyp-PDT, which strongly correlated with their inability to clear oxidatively damaged proteins. Furthermore, autophagy-attenuation in Hyp-PDT-treated cancer cells increased their ability to induce DC maturation, IL6 production and proliferation of CD4(+) or CD8(+) T cells, which was accompanied by IFNG production. Thus, our study unravels a role for ROS-induced autophagy in weakening functional interaction between dying cancer cells and the immune system thereby helping in evasion from ICD prerequisites or determinants.

Related: Cancer Prevention and Risk Reduction

Sun MM, Li JF, Guo LL, et al.
TGF-β1 suppression of microRNA-450b-5p expression: a novel mechanism for blocking myogenic differentiation of rhabdomyosarcoma.
Oncogene. 2014; 33(16):2075-86 [PubMed] Related Publications
Transforming growth factor beta 1 (TGF-β1) is the most potent inhibitor of myogenic differentiation (MyoD) of rhabdomyosarcoma (RMS); however, the underlying mechanisms of this inhibition remain unclear. In this study, we identified novel TGF-β1-related microRNAs (miRNAs); among these, miR-450b-5p is significantly regulated by TGF-β1. We provide evidence that TGF-β1 exerts it function by suppressing miR-450b-5p. Both in cultured cells and tumor implants, miR-450b-5p significantly arrested the growth of RMS and promoted its MyoD. Utilizing a bioinformatics approach, we identified miR-450b-5p target mRNAs. Among these candidates, only the expression of ecto-NOX disulfide-thiol exchanger 2 (ENOX2) and paired box 9 (PAX9) was augmented by miR-450b-5p knockdown examined by western blot; the engineered inhibition antagonized TGF-β1-mediated differentiation inhibition. Furthermore, we found that the Smad3 and Smad4 pathways, but not Smad2, are the principal mediator of TGF-β1 suppression of miR-450b-5p. Taken together, these results suggest that disrupting the TGF-β1 suppression of miR-450b-5p, or knockdown of ENOX2 and PAX9, are effective approaches in inducing RMS MyoD.

Related: Apoptosis Rhabdomyosarcoma TGFB1

Itzykson R, Solary E
An evolutionary perspective on chronic myelomonocytic leukemia.
Leukemia. 2013; 27(7):1441-50 [PubMed] Related Publications
Chronic myelomonocytic leukemia (CMML) shares with other myeloid diseases a number of somatic gene mutations. These mutations can now be integrated within the framework of evolution theory to address the mechanisms of the disease. Several evidences indicate that the disease emerges in adult hematopoietic stem cells (HSC) through the age-dependent accumulation of DNA damage, leading stochastically to a driver mutation that confers a competitive advantage to the cell. A mutation in TET2 gene could be one of these driver mutations provoking the emergence of clonality. After a long latency, secondary lesions, such as mutations in the SRSF2 gene, contribute to progression to full-blown malignancy, with abnormal differentiation. Additional mutations accumulate and branching arising mostly through mitotic recombination generates clonal heterogeneity. Modifications in the microenvironment probably affect this clonal dynamics, whereas epigenetic alterations, such as hypermethylation of the TIF1γ gene promoter, may generate phenotypic diversification of otherwise clonal populations. The preserved although deregulated myeloid differentiation that characterizes CMML, with granulomonocyte expansion and various cytopenias, may depend on early clonal dominance in the hematopietic cell hierarchy. Progression to acute myeloid leukemia observed in 25-30% of the patients may arise from the massive expansion of a clone with novel genetic lesions, providing a high fitness to previously minor subclones when in chronic phase of the disease. This review discusses the various models of disease emergence and progression and how this recent knowledge could drive rational therapeutic strategies.

Drilon A, Wang L, Hasanovic A, et al.
Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas.
Cancer Discov. 2013; 3(6):630-5 [PubMed] Free Access to Full Article Related Publications
The discovery of RET fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes. In an unselected population of non-small cell lung carcinomas (NSCLCs), RET fusions are present in 1% to 2% of cases. This incidence increases substantially, however, in never-smokers with lung adenocarcinomas that lack other known driver oncogenes. Although preclinical data provide experimental support for the use of RET inhibitors in the treatment of RET fusion-positive tumors, clinical data on response are lacking. We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospective phase II trial for patients with RET fusion-positive NSCLCs (NCT01639508). Confirmed partial responses were observed in 2 patients, including one harboring a novel TRIM33-RET fusion. A third patient with a KIF5B-RET fusion has had prolonged stable disease approaching 8 months (31 weeks). All three patients remain progression-free on treatment.

Related: Lung Cancer RET

Strauss U, Bräuer AU
Current views on regulation and function of plasticity-related genes (PRGs/LPPRs) in the brain.
Biochim Biophys Acta. 2013; 1831(1):133-8 [PubMed] Related Publications
Plasticity-related genes (PRGs, Lipid phosphate phosphatase-related proteins LPPRs) are a defined as a subclass of the lipid phosphate phosphatase (LPP) superfamily, comprising so far five brain- and vertebrate-specific membrane-spanning proteins. LPPs interfere with lipid phosphate signaling and are thereby involved in mediating the extracellular concentration and signal transduction of lipid phosphate esters such as lysophosphatidate (LPA) and spingosine-1 phosphate (S1P). LPPs dephosphorylate their substrates through extracellular catalytic domains, thus making them ecto-phosphatases. PRGs/LPPRs are structurally similar to the other LPP family members in general. They are predominantly expressed in the CNS in a subtype specific pattern rather than having a wide tissue distribution. In contrast to LPPs, PRGs/LPPRs may act by modifying bioactive lipids and their signaling pathways, rather than possessing an ecto-phosphatase activity. However, the exact functional roles of PRGs/LPPRs have just begun to be explored. Here, we discuss new findings on the neuron-specific transcriptional regulation of PRG1/LPPR4 and new insights into protein-protein interaction and signaling pathway regulation. Further, we start to shed light on the subcellular localization and the resulting functional modulatory influence of PRG1/LPPR4 expression in excitatory synaptic transmission to the established neural effects such as promotion of filopodia formation, neurite extension, axonal sprouting and reorganization after lesion. This range of effects suggests an involvement in the pathogenesis and/or reparation attempts in disease. Therefore, we summarize available data on the association of PRGs/LPPRs with several neurological and other diseases in humans and experimental animals. Finally we highlight important open questions and emerging future directions of research. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

Related: Cancer Prevention and Risk Reduction

Wen-Li Z, Jian W, Yan-Fang T, et al.
Inhibition of the ecto-beta subunit of F1F0-ATPase inhibits proliferation and induces apoptosis in acute myeloid leukemia cell lines.
J Exp Clin Cancer Res. 2012; 31:92 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Leukemia, a heterogeneous clonal disorder of hematopoietic progenitor cells, presents a world-wide health problem, especially in childhood. F1F0 ATPase, an inner mitochondrial enzyme, is expressed on the plasma membrane of tumor cells, and its inhibition induces both anti-angiogenic and anti-tumorigenic activity.
METHODS: Monoclonal Antibody (McAb) against ATPase was produced by polyethylene glycol-mediated fusions and screened by ELISA. Proliferation, cell cycle and apoptosis of cells were analyzed when the surface ATPase of cells was blockaded with McAb.
RESULTS: We detected cell-membrane expression of the F1F0 ATPase β subunit on 0.1% to 56% of the 11 cell lines derived from leukemia, including acute myeloid leukemia (AML). We produced a monoclonal antibody, McAb7E10, which recognizes both the native and recombinant ATPase β subunit, with a dissociation constant (KD) of 3.26E-10. We demonstrate that McAb7E10 binds to ATPase at the cell surface, where it is able to inhibit ATP synthesis. McAb7E10 significantly inhibited proliferation of AML cell lines in vitro: the relative inhibitory rates of 50 μg/mL McAb7E10 treated MV4-11and HL-60 cells were 69.6% and 81.9% respectively. Cell cycle analysis indicated that McAb7E10 significantly induced apoptosis in MV4-11 and HL-60 cells: the relative rates of apoptosis in 5, 10 and 50ug/mL McAb7E10 treated MV4-11 cells was 3.6 ± 0.83%, 8.4 ± 1.69% and 17.3 ± 2.56% compared to 1.5% ± 0.85% in mouse IgG treated cells (p < 0.01). The relative rate of apoptosis in 5, 10 and 50ug/mL McAb7E10 treated HL-60 cells was 5.5 ± 2.37%, 11.3 ± 3.62% and 19.9 ± 3.31% compared to 1.56% ± 0.97% in mouse IgG treated cells (p < 0.01). Annexin V staining demonstrated that the relative apoptotic rates in 50 μg/mL McAb7E10 treated MV4-11 and HL-60 cells were 50.5% ± 7.04% and 32.9% ± 4.52%, respectively, significantly higher than IgG control antibody treated cells were 21.9% ± 3.11% and 15.3% ± 3.95%, p < 0.01.
CONCLUSIONS: These findings indicate that ectopic expression of ATPase β subunit may be a tumor-associated antigen in hematological malignancies. The F1F0 ATPase β subunit provides a potential target for immunotherapy in AML and hematological malignancies.

Related: Monoclonal Antibodies Apoptosis Acute Myeloid Leukemia (AML) Mitochondrial Mutations in Cancer

Cappellari AR, Rockenbach L, Dietrich F, et al.
Characterization of ectonucleotidases in human medulloblastoma cell lines: ecto-5'NT/CD73 in metastasis as potential prognostic factor.
PLoS One. 2012; 7(10):e47468 [PubMed] Free Access to Full Article Related Publications
Medulloblastoma (MB) is the most common malignant brain tumor in children and occurs mainly in the cerebellum. Important intracellular signaling molecules, such those present in the Sonic Hedgehog and Wnt pathways, are involved in its development and can also be employed to determine tumor grade and prognosis. Ectonucleotidases, particularly ecto-5'NT/CD73, are important enzymes in the malignant process of different tumor types regulating extracellular ATP and adenosine levels. Here, we investigated the activity of ectonucleotidases in three malignant human cell lines: Daoy and ONS76, being representative of primary MB, and the D283 cell line, derived from a metastatic MB. All cell lines secreted ATP into the extracellular medium while hydrolyze poorly this nucleotide, which is in agreement with the low expression and activity of pyrophosphate/phosphodiesterase, NTPDases and alkaline phosphatase. The analysis of AMP hydrolysis showed that Daoy and ONS76 completely hydrolyzed AMP, with parallel adenosine production (Daoy) and inosine accumulation (ONS76). On the other hand, D283 cell line did not hydrolyze AMP. Moreover, primary MB tumor cells, Daoy and ONS76 express the ecto-5'NT/CD73 while D283 representative of a metastatic tumor, revealed poor expression of this enzyme, while the ecto-adenosine deaminase showed higher expression in D283 compared to Daoy and ONS76 cells. Nuclear beta-catenin has been suggested as a marker for MB prognosis. Further it can promotes expression of ecto-5'NT/CD73 and suppression of adenosine deaminase. It was observed that Daoy and ONS76 showed greater nuclear beta-catenin immunoreactivity than D283, which presented mainly cytoplasmic immunoreactivity. In summary, the absence of ecto-5'NT/CD73 in the D283 cell line, a metastatic MB phenotype, suggests that high expression levels of this ectonucleotidase could be correlated with a poor prognosis in patients with MB.

Related: Childhood Brain Tumours Childhood Brain Tumors Childhood Medulloblastoma / PNET Signal Transduction CTNNB1 gene

Takai E, Tsukimoto M, Harada H, et al.
Autocrine regulation of TGF-β1-induced cell migration by exocytosis of ATP and activation of P2 receptors in human lung cancer cells.
J Cell Sci. 2012; 125(Pt 21):5051-60 [PubMed] Related Publications
TGF-β1 plays a key role in cancer progression through induction of various biological effects, including cell migration. Extracellular nucleotides, such as ATP, released from cells play a role in signaling through activation of P2 receptors. We show here that exocytosis of ATP followed by activation of P2 receptors play a key role in TGF-β1-induced actin remodeling associated with cell migration. Treatment with TGF-β1 facilitated migration of human lung cancer A549 cells, which was blocked by pretreatment with ecto-nucleotidase and P2 receptor antagonists. ATP and P2 agonists facilitated cell migration. TGF-β1-induced actin remodeling, which contributes to cell migration, was also suppressed by pretreatment with ecto-nucleotidase and P2 receptor antagonists. Knockdown of P2X7 receptor suppressed TGF-β1-induced migration and actin remodeling. These results indicate the involvement of TGF-β1-induced ATP release in cell migration, at least in part, through activation of P2X7 receptors. TGF-β1 caused release of ATP from A549 cells within 10 minutes. Both ATP-enriched vesicles and expression of a vesicular nucleotide transporter (VNUT) SLC17A9, which is responsible for exocytosis of ATP, were found in cytosol of A549 cells. TGF-β1 failed to induce release of ATP from SLC17A9-knockdown cells. TGF-β1-induced cell migration and actin remodeling were also decreased in SLC17A9-knockdown cells. These results suggest the importance of exocytosis of ATP in cell migration. We conclude that autocrine signaling through exocytosis of ATP and activation of P2 receptors is required for the amplification of TGF-β1-induced migration of lung cancer cells.

Related: Lung Cancer Risk Factors and Prevention of Lung Cancer Signal Transduction TGFB1

Braganhol E, Wink MR, Lenz G, Battastini AM
Purinergic signaling in glioma progression.
Adv Exp Med Biol. 2013; 986:81-102 [PubMed] Related Publications
Among the pathological alterations that give tumor cells invasive potential, purinergic signaling is emerging as an important component. Studies performed in in vitro, in vivo and ex vivo glioma models indicate that alterations in the purinergic signaling are involved in the progression of these tumors. Gliomas have low expression of all E-NTPDases, when compared to astrocytes in culture. Nucleotides induce glioma proliferation and ATP, although potentially neurotoxic, does not evoke cytotoxic action on the majority of glioma cells in culture. The importance of extracellular ATP for glioma pathobiology was confirmed by the reduction in glioma tumor size by apyrase, which degrades extracellular ATP to AMP, and the striking increase in tumor size by over-expression of an ecto-enzyme that degrades ATP to ADP, suggesting the effect of extracellular ATP on the tumor growth depends on the nucleotide produced by its degradation. The participation of purinergic receptors on glioma progression, particularly P2X(7), is involved in the resistance to ATP-induced cell death. Although more studies are necessary, the purinergic signaling, including ectonucleotidases and receptors, may be considered as future target for glioma pharmacological or gene therapy.

Related: Signal Transduction

Lo Nigro C, Monteverde M, Lee S, et al.
NT5E CpG island methylation is a favourable breast cancer biomarker.
Br J Cancer. 2012; 107(1):75-83 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Relapse risk assessment and individual treatment recommendations remain suboptimal for breast cancer patients. In the light of existing preclinical and clinical data, we studied NT5E (5'-nucleotidase, ecto) expression and NT5E CpG island methylation in breast cancer.
METHODS: We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse NT5E in breast carcinoma cell lines and primary and breast carcinomas.
RESULTS: NT5E CpG island methylation was inversely associated with NT5E expression in breast carcinoma cell lines. In clinical series, patients whose primary tumours had NT5E CpG island methylation were less likely to develop metastasis (P=0.003, OR=0.34, 95% CI: 0.17-0.69). In 3/4 paired samples, NT5E was methylated in primary tumours and demethylated in CNS metastases. Patients progressing to non-visceral as compared with visceral metastases were more likely to have NT5E CpG island methylation in primary tumours (P=0.01, OR=11.8). Patients with tumours lacking detectable methylation had shorter disease-free survival (DFS) (P=0.001, HR=2.7) and overall survival (OS) (P=0.001, HR=3). The favourable prognostic value of NT5E methylation was confirmed in oestrogen receptor negative (P=0.011, HR=3.27, 95% CI: 1.31-8.12) and in triple negative cases (P=0.004; HR=6.2, 95% CI: 1.9-20). Moreover, we observed a more favourable outcome to adjuvant chemotherapy in patients whose tumours were positive for NT5E CpG island methylation: DFS (P=0.0016, HR=5.1, 95% CI: 1.8-14.37) and OS (P=0.0005, HR=7.4, 95% CI: 2.416-23.08).
CONCLUSION: NT5E CpG island methylation is a promising breast cancer biomarker.

Related: Breast Cancer

Supernat A, Markiewicz A, Welnicka-Jaskiewicz M, et al.
CD73 expression as a potential marker of good prognosis in breast carcinoma.
Appl Immunohistochem Mol Morphol. 2012; 20(2):103-7 [PubMed] Related Publications
Ecto-5'-nucleotidase (CD73) is a membrane-bound enzyme, which catalyzes the conversion of adenosine monophosphate to adenosine. CD73 has been postulated to play an important role in carcinogenesis, as adenosine promotes tumor progression and CD73-expressing cancer cell lines are more aggressive. However, other studies have shown that activated adenosine receptors may also inhibit cell proliferation. This study investigated the clinical significance of CD73 expression in breast cancer. The study group included 136 consecutive stage I-III breast cancer patients treated between 2001 and 2008 at 2 institutions. CD73 expression was examined by immunohistochemistry (IHC) on tissue microarrays, using antihuman mouse monoclonal antibody. Survival curves were generated by the Kaplan-Meier method and compared using the log-rank test. CD73 staining was expressed as the score calculated by multiplying the staining intensity (0=negative, 1=weak, 2=intermediate, 3=strong) and percentage of positive cells (0% to 100%). The median score among all samples was 100. Positive CD73 staining (defined as score equal or higher than 100) occurred in 74% of the cases. No correlation was found between CD73 expression and grading, tumor size, lymph node status, histologic type, estrogen receptor, or progesterone receptor status. Positive CD73 expression strongly correlated with longer disease-free survival (hazard ratio=0.26; 95% confidence interval, 0.1-0.66; P=0.0044) and overall survival (hazard ratio =0.24; 95% confidence interval, 0.07-0.85; P=0.027). Multivariate analysis for disease-free survival revealed correlation with tumor size and CD73 status. Elevated CD73 expression in breast cancer can predict a good prognosis. However, the actual role of CD73 in cancerogenesis remains unclear and requires further analysis.

Related: Breast Cancer

Wang H, Lee S, Nigro CL, et al.
NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity.
Br J Cancer. 2012; 106(8):1446-52 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Novel prognostic biomarkers and therapeutic strategies are urgently required for malignant melanoma. Ecto-5-prime-nucleotidase (NT5E; CD73) overexpression has been reported in several human cancers. The mechanism(s) underlying deregulated expression and the clinical consequences of changes in expression are not known.
METHODS: We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse expression and regulation of NT5E in malignant melanoma cell lines and primary and metastatic melanomas.
RESULTS: NT5E is subject to epigenetic regulation in melanoma. NT5E mRNA is downregulated by methylation-dependent transcriptional silencing in the melanoma cell lines SKMel2, SKMel23, WM35, Mel501, Mel505 and C81-61 and expression is reactivated by azacytidine. In contrast, the CpG island is unmethylated and the gene expressed in cultured normal melanocytes. In clinical cases of melanoma, methylation in the NT5E CpG island occurs in both primary and metastatic melanomas and correlates with transcriptional downregulation of NT5E mRNA. Relapse with metastatic disease, particularly to the visceral sites and brain, is more common in primary melanomas lacking NT5E methylation. Primary melanomas with methylation in NT5E show limited metastatic potential or more commonly metastasise predominantly to nodal sites rather than viscera and brain (P=0.01).
CONCLUSION: Deregulation of NT5E expression in melanoma occurs via epigenetic changes in the NT5E CpG island. Confirmation of our results in larger clinical series would support the candidacy of NT5E as a clinical biomarker in melanoma, which could be applied in both primary and relapsed disease. Inhibition of NT5E may have therapeutic potential in melanoma, particularly in patients with more aggressive disease metastatic to viscera or the brain.

Related: Melanoma

Martins I, Michaud M, Sukkurwala AQ, et al.
Premortem autophagy determines the immunogenicity of chemotherapy-induced cancer cell death.
Autophagy. 2012; 8(3):413-5 [PubMed] Related Publications
One particular strategy to render anticancer therapies efficient consists of converting the patient's own tumor cells into therapeutic vaccines, via the induction of immunogenic cell death (ICD). One of the hallmarks of ICD dwells in the active release of ATP by cells committed to undergo, but not yet having succumbed to, apoptosis. We observed that the knockdown of essential autophagy-related genes (ATG3, ATG5, ATG7 and BECN1) abolishes the pre-apoptotic secretion of ATP by several human and murine cancer cell lines undergoing ICD. Accordingly, autophagy-competent, but not autophagy-deficient, tumor cells treated with ICD inducers in vitro could induce a tumor-specific immune response in vivo. Cancer cell lines stably depleted of ATG5 or ATG7 normally generate tumors in vivo, and such autophagy-deficient neoplasms, upon systemic treatment with ICD inducers, exhibit the same levels of apoptosis (as monitored by nuclear shrinkage and caspase-3 activation) and necrosis (as determined by following the kinetics of HMGB1 release) as their autophagy-proficient counterparts. However, autophagy-incompetent cancers fail to release ATP, to recruit immune effectors into the tumor bed and to respond to chemotherapy in conditions in which autophagy-competent tumors do so. The intratumoral administration of ecto-ATPase inhibitors increases extracellular ATP concentrations, re-establishes the therapy-induced recruitment of dendritic cells and T cells into the tumor bed, and restores the chemotherapeutic response of autophagy-deficient cancers. Altogether, these results suggest that autophagy-incompetent tumor cells escape from chemotherapy-induced (and perhaps natural?) immunosurveillance because they are unable to release ATP.

Related: Cancer Prevention and Risk Reduction

Pan J, Sun LC, Tao YF, et al.
ATP synthase ecto-α-subunit: a novel therapeutic target for breast cancer.
J Transl Med. 2011; 9:211 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Treatment failure for breast cancer is frequently due to lymph node metastasis and invasion to neighboring organs. The aim of the present study was to investigate invasion- and metastasis-related genes in breast cancer cells in vitro and in vivo. Identification of new targets will facilitate the developmental pace of new techniques in screening and early diagnosis. Improved abilities to predict progression and metastasis, therapeutic response and toxicity will help to increase survival of breast cancer patients.
METHODS: Differential protein expression in two breast cancer cell lines, one with high and the other with low metastatic potential, was analyzed using two-dimensional liquid phase chromatographic fractionation (Proteome Lab PF 2D system) followed by matrix-assisted laser desorption/time-of-flight mass spectrometry (MALDI-TOF/MS).
RESULTS: Up regulation of α-subunit of ATP synthase was identified in high metastatic cells compared with low metastatic cells. Immunohistochemical analysis of 168 human breast cancer specimens on tissue microarrays revealed a high frequency of ATP synthase α-subunit expression in breast cancer (94.6%) compared to normal (21.2%) and atypical hyperplasia (23%) breast tissues. Levels of ATP synthase expression levels strongly correlated with large tumor size, poor tumor differentiation and advanced tumor stages (P < 0.05). ATP synthase α-subunit over-expression was detected on the surface of a highly invasive breast cancer cell line. An antibody against the ATP synthase α-subunit inhibited proliferation, migration and invasion in these breast cancer cells but not that of a non-tumor derived breast cell line.
CONCLUSIONS: Over-expression of ATP synthase α-subunit may be involved in the progression and metastasis of breast cancer, perhaps representing a potential biomarker for diagnosis, prognosis and a therapeutic target for breast cancer. This finding of this study will help us to better understand the molecular mechanism of tumor metastasis and to improve the screening, diagnosis, as well as prognosis and/or prediction of responses to therapy for breast cancer.

Related: Apoptosis Breast Cancer

Hatakeyama S
TRIM proteins and cancer.
Nat Rev Cancer. 2011; 11(11):792-804 [PubMed] Related Publications
Emerging clinical evidence shows that the deregulation of ubiquitin-mediated degradation of oncogene products or tumour suppressors is likely to be involved in the aetiology of carcinomas and leukaemias. Recent studies have indicated that some members of the tripartite motif (TRIM) proteins (one of the subfamilies of the RING type E3 ubiquitin ligases) function as important regulators for carcinogenesis. This Review focuses on TRIM proteins that are involved in tumour development and progression.

Related: Cancer Prevention and Risk Reduction PML gene

Braun T, Itzykson R, Renneville A, et al.
Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial.
Blood. 2011; 118(14):3824-31 [PubMed] Related Publications
Hydroxyurea is the standard therapy of chronic myelomonocytic leukemia (CMML) presenting with advanced myeloproliferative and/or myelodysplastic features. Response to hypomethylating agents has been reported in heterogeneous series of CMML. We conducted a phase 2 trial of decitabine (DAC) in 39 patients with advanced CMML defined according to a previous trial. Median number of DAC cycles was 10 (range, 1-24). Overall response rate was 38% with 4 complete responses (10%), 8 marrow responses (21%), and 3 stable diseases with hematologic improvement (8%). Eighteen patients (46%) demonstrated stable disease without hematologic improvement, and 6 (15%) progressed to acute leukemia. With a median follow-up of 23 months, overall survival was 48% at 2 years. Mutations in ASXL1, TET2, AML1, NRAS, KRAS, CBL, FLT3, and janus kinase 2 (JAK2) genes, and hypermethylation of the promoter of the tumor suppressor gene TIF1γ, did not predict response or survival on DAC therapy. Lower CJUN and CMYB gene expression levels independently predicted improved overall survival. This trial confirmed DAC efficacy in approximately 40% of CMML patients with advanced myeloproliferative or myelodysplastic features and suggested that CJUN and CMYB expression could be potential biomarkers in this setting. This trial is registered at EudraCT (eudract.ema.europa.eu) as #2008-000470-21 and www.clinicaltrials.gov as #NCT01098084.

Related: Azacitidine

Aucagne R, Droin N, Paggetti J, et al.
Transcription intermediary factor 1γ is a tumor suppressor in mouse and human chronic myelomonocytic leukemia.
J Clin Invest. 2011; 121(6):2361-70 [PubMed] Free Access to Full Article Related Publications
Transcription intermediary factor 1γ (TIF1γ) was suggested to play a role in erythropoiesis. However, how TIF1γ regulates the development of different blood cell lineages and whether TIF1γ is involved in human hematological malignancies remain to be determined. Here we have shown that TIF1γ was a tumor suppressor in mouse and human chronic myelomonocytic leukemia (CMML). Loss of Tif1g in mouse HSCs favored the expansion of the granulo-monocytic progenitor compartment. Furthermore, Tif1g deletion induced the age-dependent appearance of a cell-autonomous myeloproliferative disorder in mice that recapitulated essential characteristics of human CMML. TIF1γ was almost undetectable in leukemic cells of 35% of CMML patients. This downregulation was related to the hypermethylation of CpG sequences and specific histone modifications in the gene promoter. A demethylating agent restored the normal epigenetic status of the TIF1G promoter in human cells, which correlated with a reestablishment of TIF1γ expression. Together, these results demonstrate that TIF1G is an epigenetically regulated tumor suppressor gene in hematopoietic cells and suggest that changes in TIF1γ expression may be a biomarker of response to demethylating agents in CMML.

Related: Azacitidine CSF1R

Aerts I, Martin JJ, De Deyn PP, et al.
The expression of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (E-NPP1) is correlated with astrocytic tumor grade.
Clin Neurol Neurosurg. 2011; 113(3):224-9 [PubMed] Related Publications
OBJECTIVE: Astrocytic brain tumors are subdivided in four grades. The most aggressive and invasive one is grade IV or glioblastoma multiforme (GBM). Ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (E-NPP1), a membrane-bound enzyme, is involved in many cellular processes such as modulation of purinergic signalling, nucleotide recycling, regulation of extracellular pyrophosphate levels and stimulation of cell motility. In this study, the use of anti-NPP1 antibody in the determination of astrocytic tumor grade is evaluated.
MATERIALS AND METHODS: Paraffin-embedded surgical specimens from 41 primary human astrocytic brain tumors (grade I=2; grade II=10; grade III=9; grade IV=20) and 5 control samples are immunostained against NPP1 and glial fibrillary acid protein an astrocytic marker.
RESULTS: In this communication, we report the expression of NPP1 in human astrocytic brain tumors. No expression could be detected in control tissue. We observed a remarkable up regulated expression of NPP1 in GBM. Taking the latter as 100%, grade I has a relative NPP1 staining of 7%, whereas grade II and III have a similar NPP1 expression level of 53% and 47% respectively.
CONCLUSION: A correlation is found between the up-regulated expression of NPP1 and the grade of the astrocytic tumor. Further investigation of NPP1 expression, especially in GBM, is necessary to determine the role of NPP1 in astrocytic brain tumor progression.

Spina C, Saccucci P, Cozzoli E, et al.
A study of three polymorphic sites of ADA gene in colon cancer.
Cancer Invest. 2010; 28(10):989-92 [PubMed] Related Publications
Adenosine inhibits the immune response in tumors. Adenosine deaminase (ADA) controls adenosine level and as ecto-enzyme acts as costimulatory molecule of adenosine receptors and/or CD26. We examined ADA₁, ADA₂, ADA₆ polymorphic sites of ADA gene in 109 subjects with colon cancer from Rome's population and in 246 blood donors as controls from the same population. In colon cancer ADA₁*2/ADA₂*1 haplotype is more represented, while ADA₁*2/ADA₂*2 is less represented than in controls. ADA₂*2/ADA₆*2 is less represented in patients than in controls. Polymorphic sites of ADA might influence cell-mediated anti-tumor immune responses controlling adenosine level and extraenzymatic protein functions.

Lunde ML, Warnakulasuriya S, Sand L, et al.
Gene expression analysis by cDNA microarray in oral cancers from two Western populations.
Anticancer Res. 2010; 30(4):1083-91 [PubMed] Related Publications
BACKGROUND: In this work, gene expression profile was examined in 19 cases of oral cancer (OC) obtained from patients from Sweden (n=8) and UK (n=11) and the findings were tested for correlation to patient's clinicopathological data.
MATERIALS AND METHODS: Following total RNA extraction, cDNA synthesis, labeling with fluorescent dyes and hybridization to the 21 k human oligonucleotide microarrays, slides were scanned and images were subjected to Genepix and J-Express analysis. Results for selected genes were validated by quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR).
RESULTS: 42 genes were identified as being differentially expressed. These included 39 genes of known functions (such as fatty acid synthase (FASN), 5' nucleotidase, ecto (NT5E), high mobility group AT-hook (HMGA1), and v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS)) and 3 novel genes; 26 (67%) of the 39 genes with known functions were previously reported in oral/head and neck tumors examined from other populations. Hierarchical clustering of the samples using the 42 genes demonstrated that samples mainly clustered in the same population.
CONCLUSION: These results illustrate that microarrays can be used to identify distinct patterns of gene expression in different populations, but with no direct association to clinicopathological parameters. The fact that 67% of the 39 genes with known functions found in this work were previously reported in oral/head and neck tumors from other populations provides clear evidence that development of these tumors follows the same biological pathways irrespective of the source of the samples used.

Related: Oral Cancer

Vincent DF, Yan KP, Treilleux I, et al.
Inactivation of TIF1gamma cooperates with Kras to induce cystic tumors of the pancreas.
PLoS Genet. 2009; 5(7):e1000575 [PubMed] Free Access to Full Article Related Publications
Inactivation of the Transforming Growth Factor Beta (TGFbeta) tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC) since it is inactivated in virtually all cases of this malignancy. Genetic lesions inactivating this pathway contribute to pancreatic tumor progression in mouse models. Transcriptional Intermediary Factor 1 gamma (TIF1gamma) has recently been proposed to be involved in TGFbeta signaling, functioning as either a positive or negative regulator of the pathway. Here, we addressed the role of TIF1gamma in pancreatic carcinogenesis. Using conditional Tif1gamma knockout mice (Tif1gamma(lox/lox)), we selectively abrogated Tif1gamma expression in the pancreas of Pdx1-Cre;Tif1gamma(lox/lox) mice. We also generated Pdx1-Cre;LSL-Kras(G12D);Tif1gamma(lox/lox) mice to address the effect of Tif1gamma loss-of-function in precancerous lesions induced by oncogenic Kras(G12D). Finally, we analyzed TIF1gamma expression in human pancreatic tumors. In our mouse model, we showed that Tif1gamma was dispensable for normal pancreatic development but cooperated with Kras activation to induce pancreatic tumors reminiscent of human Intraductal Papillary Mucinous Neoplasms (IPMNs). Interestingly, these cystic lesions resemble those observed in Pdx1-Cre;LSL-Kras(G12D);Smad4(lox/lox) mice described by others. However, distinctive characteristics, such as the systematic presence of endocrine pseudo-islets within the papillary projections, suggest that SMAD4 and TIF1gamma don't have strictly redundant functions. Finally, we report that TIF1gamma expression is markedly down-regulated in human pancreatic tumors by quantitative RT-PCR and immunohistochemistry supporting the relevance of these findings to human malignancy. This study suggests that TIF1gamma is critical for tumor suppression in the pancreas, brings new insight into the genetics of pancreatic cancer, and constitutes a promising model to decipher the respective roles of SMAD4 and TIF1gamma in the multifaceted functions of TGFbeta in carcinogenesis and development.

Related: Cancer of the Pancreas Pancreatic Cancer

Almog N, Ma L, Raychowdhury R, et al.
Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype.
Cancer Res. 2009; 69(3):836-44 [PubMed] Related Publications
Tumor dormancy has important implications for early detection and treatment of cancer. Lack of experimental models and limited clinical accessibility constitute major obstacles to the molecular characterization of dormant tumors. We have developed models in which human tumors remain dormant for a prolonged period of time (>120 days) until they switch to rapid growth and become strongly angiogenic. These angiogenic tumors retain their ability to grow fast once injected in new mice. We hypothesized that dormant tumors undergo a stable genetic reprogramming during their switch to the fast-growing phenotype. Genome-wide transcriptional analysis was done to dissect the molecular mechanisms underlying the switch of dormant breast carcinoma, glioblastoma, osteosarcoma, and liposarcoma tumors. A consensus expression signature distinguishing all four dormant versus switched fast-growing tumors was generated. In alignment with our phenotypic observation, the angiogenesis process was the most significantly affected functional gene category. The switch of dormant tumors was associated with down-regulation of angiogenesis inhibitor thrombospondin and decreased sensitivity of angiogenic tumors to angiostatin. The conversion of dormant tumors to exponentially growing tumors was also correlated with regulation and activation of pathways not hitherto linked to tumor dormancy process, such as endothelial cell-specific molecule-1, 5'-ecto-nucleotidase, tissue inhibitor of metalloproteinase-3, epidermal growth factor receptor, insulin-like growth factor receptor, and phosphatidylinositol 3-kinase signaling. Further, novel dormancy-specific biomarkers such as H2BK and Eph receptor A5 (EphA5) were discovered. EphA5 plasma levels in mice and mRNA levels in tumor specimens of glioma patients correlated with diseases stage. These data will be instrumental in identifying novel early cancer biomarkers and could provide a rationale for development of dormancy-promoting tumor therapy strategies.

Related: Cancer Prevention and Risk Reduction Angiogenesis and Cancer EPHA5

Shi Y, Sun X, Chen Z, et al.
Association of the polymorphism of codon 121 in the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 gene with polycystic ovary syndrome in Chinese women.
Saudi Med J. 2008; 29(8):1119-23 [PubMed] Related Publications
OBJECTIVE: To determine the association of polymorphism of codon 121 in the ecto-nucleotide pyrophophastase/phosphodiesterase 1 (E-NPP1/PC-1) gene in Chinese women with polycystic ovary syndrome (PCOS).
METHODS: A total of 51 PCOS patients and 61 healthy women from the Chinese Han population from the Center Reproductive Medicine of Provincial Hospital affiliated to Shandong University from June 2005 to July 2006 were recruited for the determination of the polymorphism of the E-NPP1/PC-1 gene. Genomic DNA was extracted from peripheral blood monocytes of patients and controls, and genotyping of the gene was performed by using polymerase chain reaction, which was followed by sequencing.
RESULTS: The frequency of the 121Q allele was 13 and 18%, respectively, in PCOS patients and healthy women, while the frequency of the 121K allele was 87 and 82% in the 2 groups. There is no significant difference in the E-NPP1/PC-1 polymorphism between PCOS patients and healthy controls among Chinese Han women.
CONCLUSION: Ecto-nucleotide pyrophophastase/phosphodiesterase 1 polymorphism has no association with PCOS. Further studies are still needed to elucidate whether or not the E-NPP1/PC-1 gene has a functional role in PCOS.

Related: Polymorphisms

Bavaresco L, Bernardi A, Braganhol E, et al.
The role of ecto-5'-nucleotidase/CD73 in glioma cell line proliferation.
Mol Cell Biochem. 2008; 319(1-2):61-8 [PubMed] Related Publications
Malignant gliomas are the most common and devastating primary tumors in the brain and, despite treatment, patients with these tumors have a poor prognosis. The participation of ecto-5'-NT/CD73 per se as a proliferative factor, being involved in the control of cell growth, differentiation, invasion, migration and metastasis processes has been previously proposed. In the present study, we evaluated the activity and functions of ecto-5'-NT/CD73 during the proliferation process of rat C6 and human U138MG glioma cell lines. Increasing confluences and culture times led to an increase in ecto-5'-NT/CD73 activity in both C6 and U138MG glioma cells. RT-PCR analysis and flow cytometry analysis showed a significant increase in ecto-5'-NT/CD73 mRNA and protein levels, respectively, comparing confluent with sub-confluent cultures in human U138MG glioma cells. Ecto-5'-nucleotidase/CD73 may regulate the extracellular adenosine 5'-monophosphate (AMP) and adenosine levels. Treatment with 1 microM APCP, a competitive ecto-5'-NT/CD73 inhibitor, caused a significant reduction of 30% in glioma cell proliferation. In addition, 100 microM adenosine increases cell proliferation by 36%, and the treatment with adenosine plus NBTI and dipyridamole, produced an additional and significant increase of on cell proliferation. The inhibitory effect on cell proliferation caused by APCP was reverted by co-treatment with NBTI and dipyridamole. AMP (1 mM and 3 mM) decreased U138MG glioma cell proliferation by 29% and 42%, respectively. Taken together, these results suggest the participation of ecto-5'-NT/CD73 in cell proliferation and that this process is dependent upon the enzyme's production of adenosine, a proliferative factor, and removal of AMP, a toxic molecule for gliomas.

Tonino SH, Spijker R, Luijks DM, et al.
No convincing evidence for a role of CD31-CD38 interactions in the pathogenesis of chronic lymphocytic leukemia.
Blood. 2008; 112(3):840-3 [PubMed] Related Publications
Although CD38, a marker of poor prognosis in chronic lymphocytic leukemia (CLL), is known primarily as an ecto-enzyme, it has also been ascribed a receptor function. Interaction with its proposed ligand CD31 expressed on nurse-like cells would result in proliferative and survival-signals. Yet, in CLL, both homotypic and heterotypic CD31-CD38 interactions are expected to be rather ubiquitous. We analyzed whether CD38-CD31 interactions result in proliferative and antiapoptotic signals. We found a high expression of CD31 on CLL, irrespective of CD38 expression. Coculture of CD38(high) CLL with endothelial cells or CD31 transfected fibroblasts, with or without blocking CD31 or CD38 antibodies, did not result in increased survival or proliferation. Analysis of gene expression of most known regulators of apoptosis revealed no influence of coculture with CD31-expressing feeder cells. In conclusion, our data do not support an important contribution of CD38 triggering by CD31 to the proliferative and antiapoptotic state of the leukemic clone.

Related: Apoptosis Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Signal Transduction


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Cite this page: Cotterill SJ. TRIM33 gene, Cancer Genetics Web: http://www.cancerindex.org/geneweb/TRIM33.htm Accessed: date

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