Sémaphorines et cancers : état des lieux

Les sémaphorines jouent un rôle central dans le guidage axonal, la régénération axonale chez l'adulte et le développement de certains tissus. De plus, la découverte de leur implication dans l'angiogenèse et la réponse immunitaire indique une fonction beaucoup plus large de ces protéines. En 1996, trois études concomitantes ont permis de cloner les gènes codant pour deux de ces protéines, SEMA3B et SEMA3F, dans la région 3p21.3 qui subit de fréquentes pertes d'hétérozygotie dans les cancers du sein et du poumon. L'hypothèse avait alors été émise selon laquelle ces gènes pouvaient être des suppresseurs de tumeurs. Les études ultérieures ont confirmé ce rôle. à l'inverse, d'autres sémaphorines stimuleraient la croissance tumorale. Cet article fait le point sur les dernières connaissances acquises concernant le rôle des sémaphorines dans les cancers. Il souligne en particulier les propriétés anti-migratoires et anti-angiogéniques de ces molécules, qui pourraient jouer un rôle déterminant dans l'inhibition de la formation de métastases.Semaphorins, first described as axon guidance molecules, play an essential role in neural development, angiogenesis and immunological response. In 1996, two semaphorin genes, SEMA3B and SEMA3F, were isolated from chromosomal region 3p21.3 believed to contain a tumor suppressor gene based on frequent loss of heterozygosity in lung and breast cancer. Since these first studies, several semaphorins have been involved in tumor progression. Some semaphorins have been proposed to have pro-tumoral properties, whereas others have been shown to have tumor suppressive activity. This review summarizes the most recent data implicating semaphorins in cancers

The tumor suppressor gene TRC8/RNF139 is disrupted by a constitutional balanced translocation t(8;22)(q24.13;q11.21) in a young girl with dysgerminoma

<p>Abstract</p> <p>Background</p> <p><it>RNF139/TRC8 </it>is a potential tumor suppressor gene with similarity to PTCH, a tumor suppressor implicated in basal cell carcinomas and glioblastomas. <it>TRC8 </it>has the potential to act in a novel regulatory relationship linking the cholesterol/lipid biosynthetic pathway with cellular growth control and has been identified in families with hereditary renal (RCC) and thyroid cancers. Haploinsufficiency of <it>TRC8 </it>may facilitate development of clear cell-RCC in association with <it>VHL </it>mutations, and may increase risk for other tumor types. We report a paternally inherited balanced translocation t(8;22) in a proposita with dysgerminoma.</p> <p>Methods</p> <p>The translocation was characterized by FISH and the breakpoints cloned, sequenced, and compared. DNA isolated from normal and tumor cells was checked for abnormalities by array-CGH. Expression of genes <it>TRC8 </it>and <it>TSN </it>was tested both on dysgerminoma and in the proposita and her father.</p> <p>Results</p> <p>The breakpoints of the translocation are located within the LCR-B low copy repeat on chromosome 22q11.21, containing the palindromic AT-rich repeat (PATRR) involved in recurrent and non-recurrent translocations, and in an AT-rich sequence inside intron 1 of the TRC8 tumor-suppressor gene at 8q24.13. <it>TRC8 </it>was strongly underexpressed in the dysgerminoma. Translin is underexpressed in the dysgerminoma compared to normal ovary.</p> <p><it>TRC8 </it>is a target of Translin (TSN), a posttranscriptional regulator of genes transcribed by the transcription factor CREM-tau in postmeiotic male germ cells.</p> <p>Conclusion</p> <p>A role for <it>TRC8 </it>in dysgerminoma may relate to its interaction with Translin. We propose a model in which one copy of <it>TRC8 </it>is disrupted by a palindrome-mediated translocation followed by complete loss of expression through suppression, possibly mediated by miRNA.</p

Homeobox gene expression in acute myeloid leukemia is linked to typical underlying molecular aberrations

Background: Although distinct patterns of homeobox (HOX) gene expression have been described in defined cytogenetic and molecular subsets of patients with acute myeloid leukemia (AML), it is unknown whether these patterns are the direct result of transcriptional alterations or rather represent the differentiation stage of the leukemic cell. Method: To address this question, we used qPCR to analyze mRNA expression of HOXA and HOXB genes in bone marrow (BM) samples of 46 patients with AML and sorted subpopulations of healthy BM cells. These various stages of myeloid differentiation represent matched counterparts of morphological subgroups of AML. To further study the transcriptional alterations of HOX genes in hematopoiesis, we also analyzed gene expression of epigenetic modifiers in the subpopluations of healthy BM and leukemic cells. Results: Unsupervised hierarchical clustering divided the AMLs into five clusters characterized by the presence of prevalent molecular genetic aberrations. Notably, the impact of genotype on HOX gene expression was significantly more pronounced than that of the differentiation stage of the blasts. This driving role of molecular aberrations was best exemplified by the repressive effect of the PML-RARa fusion gene on HOX gene expression, regardless of the presence of the FLT3/ITD mutation. Furthermore, HOX gene expression was positively correlated with mRNA levels of histone demethylases (JMJD3 and UTX) and negatively correlated with gene expression of DNA methyltranferases. No such relationships were observed in subpopulations of healthy BM cells. Conclusion: Our results demonstrate that specific molecular genetic aberrations, rather than differentiation per se, underlie the observed differences in HOX gene expression in AML. Moreover, the observed correlations between epigenetic modifiers and HOX ex pression that are specific to malignant hematopoiesis, suggest their potential causal relationships.</p

Isolation of DNA sequences on human chromosome 21 by application of a recombination-based assay to DNA from flow-sorted chromosomes

By merging two efficient technologies, bivariate flow sorting of human metaphase chromosomes and a recombination-based assay for sequence complexity, we isolated 28 cloned DNA segments homologous to loci on human chromosome 21. Subregional mapping of these DNA segments with a somatic cell hybrid panel showed that 26 of the 28 cloned DNA sequences are distributed along the long arm of chromosome 21, while the other 2 hybridize with sequences on the short arm of both chromosome 21 and other chromosomes. This new collection of probes homologous to chromosome 21 should facilitate molecular analyses of trisomy 21 by providing DNA probes for the linkage map of chromosome 21, for studies of nondisjunction, for chromosome walking in clinically relevant subregions of chromosome 21, and for the isolation of genes on chromosome 21 following the screening of cDNA libraries.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47623/1/439_2004_Article_BF00366237.pd

The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER

Human cytomegalovirus uses an E3 ubiquitin ligase to divert MHC I molecules into the ER-associated degradation pathway for destruction

Epigenetic Regulation of the Epithelial to Mesenchymal Transition in Lung Cancer

Lung cancer is the leading cause of cancer deaths worldwide. It is an aggressive and devastating cancer because of metastasis triggered by enhanced migration and invasion, and resistance to cytotoxic chemotherapy. The epithelial to mesenchymal transition (EMT) is a fundamental developmental process that is reactivated in wound healing and a variety of diseases including cancer where it promotes migration/invasion and metastasis, resistance to treatment, and generation and maintenance of cancer stem cells. The induction of EMT is associated with reprogramming of the epigenome. This review focuses on major mechanisms of epigenetic regulation mainly in lung cancer with recent data on EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit ), the catalytic subunit of the PRC2 (Polycomb Group PcG), that behaves as an oncogene in lung cancer associated with gene repression, non-coding RNAs and the epitranscriptome

Semaphorin SEMA3F Has a Repulsing Activity on Breast Cancer Cells and Inhibits E-Cadherin-Mediated Cell Adhesion

Previously, we demonstrated that loss of SEMA3F, a secreted semaphorin encoded in 3p21.3, is associated with higher stages in lung cancer and primary tumor cells studied with anti-vascular endothelial growth factor (VEGF) and SEMA3F antibodies. In vitro, SEMA3F inhibits cell spreading; this activity is opposed by VEGF. These results suggest that VEGF and SEMA3F compete for binding to their common neuropilin receptor. In the present report, we investigated the attractive/repulsive effects of SEMA3F on cell migration when cells were grown in a three-dimensional system and exposed to a SEMA3F gradient. In addition, we adapted the neurobiologic stripe assay to analyze the migration of tumor cells in response to SEMA3F. In the motile breast cancer cell line C100, which expresses both neuropilin-1 (NRP1) and neuropilin-2 (NRP2) receptors, SEMA3F had a repulsive effect, which was blocked by anti-NRP2 antibody. In less motile MCF7 cells, which express only NRP1, SEMA3F inhibited cell contacts with loss of membrane-associated E-cadherin and β-catenin without motility induction. Cell spreading and proliferation were reduced. These results support the concept that in a first step during tumorigenesis, normal tissues expressing SEMA3F would try to prevent tumor cells from spreading and attaching to the stroma for further implantation

Semaphorin SEMA3F and VEGF Have Opposing Effects on Cell Attachment and Spreading

SEMA3F, isolated from a 3p21.3 deletion, has antitumor activity in transfected cells, and protein expression correlates with tumor stage and histology. In primary tumors, SEMA3F and VEGF surface staining is inversely correlated. Coupled with SEMA3F at the leading edge of motile cells, we previously suggested that both proteins competitively regulate cell motility and adhesion. We have investigated this using the breast cancer cell line, MCF7. SEMA3F inhibited cell attachment and spreading as evidenced by loss of lamellipodia extensions, membrane ruffling, and cell-cell contacts, with cells eventually rounding-up and detaching. In contrast, VEGF had opposite effects. Although SEMA3F binds NRP2 with 10-fold greater affinity than NRP1, the effects in MCF7 were mediated by NRP1. This was determined by receptor expression and blocking of anti-NRP1 antibodies. Similar effects, but through NRP2, were observed in the C100 breast cancer cell line. Although we were unable to demonstrate changes in total GTP-bound Rac1 or RhoA, we did observe changes in the localization of Rac1-GFP using time lapse microscopy. Following SEMA3F, Rac1 moved to the base of lamellipodia and — with their collapse — to the membrane. These results support the concept that SEMA3F and VEGF have antagonistic actions affecting motility in primary tumor cell

ZEB-1, a Repressor of the Semaphorin 3F Tumor Suppressor Gene in Lung Cancer Cells

SEMA3F is a secreted semaphorin with potent antitumor activity, which is frequently downregulated in lung cancer. In cancer cell lines, SEMA3F overexpression decreases hypoxia-induced factor 1α protein and vascular endothelial growth factor mRNA, and inhibits multiple signaling components. Therefore, understanding how SEMA3F expression is inhibited in cancer cells is important. We previously defined the promoter organization of SEMA3F and found that chromatin remodeling by a histone deacetylase inhibitor was sufficient to activate SEMA3F expression. In lung cancer, we have also shown that ZEB-1, an E-box transcription repressor, is predominantly responsible for loss of E-Cadherin associated with a poor prognosis and resistance to epidermal growth factor receptor inhibitors. In the present study, we demonstrated that ZEB-1 also inhibits SEMA3F in lung cancer cells. Levels of ZEB-1, but not ZEB-2, Snail or Slug, significantly correlate with SEMA3F inhibition, and overexpression or inhibition of ZEB-1 correspondingly affected SEMA3F expression. Four conserved E-box sites were identified in the SEMA3F gene. Direct ZEB-1 binding was confirmed by chromatin immunoprecipitation assays for two of these, and ZEB-1 binding was reduced when cells were treated with a histone deacetylase inhibitor. These results demonstrate that ZEB-1 directly inhibits SEMA3F expression in lung cancer cells. SEMA3F loss was associated with changes in cell signaling: increased phospho-AKT in normoxia and increase of hypoxia-induced factor 1α protein in hypoxia. Moreover, exogenous addition of SEMA3F could modulate ZEB-1-induced angiogenesis in a chorioallantoic membrane assay. Together, these data provide further support for the importance of SEMA3F and ZEB-1 in lung cancer progression