The epithelial-mesenchymal transition-inducing factor TWIST is an attractive target in advanced and/or metastatic bladder and prostate cancers

Wallerand, Hervé; Gáspár, Róbert; Pasticier, G.; Ravaud, Alain; Ballanger, P.; Reiter, Robert E.; Ferrière, Jean-Marie

doi:10.1016/j.urolonc.2008.12.018

Cited by 96 publications

(73 citation statements)

References 46 publications

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“…Other epithelial markers, ZO-1 and occluding, were not detected, whereas cytokeratin-18 was unchanged in either cell line, indicating that Ecad is the principal epithelial marker downregulated during EMT process in prostate cells. This finding is consistent with previous studies (45)(46)(47)(48).…”

Section: Discussionsupporting

confidence: 94%

Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process

Freire-de-Lima

Gelfenbeyn

Ding

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

130

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The process termed "epithelial-mesenchymal transition" (EMT) was originally discovered in ontogenic development, and has been shown to be one of the key steps in tumor cell progression and metastasis. Recently, we showed that the expression of some glycosphingolipids (GSLs) is down-regulated during EMT in human and mouse cell lines. Here, we demonstrate the involvement of GalNAc-type (or mucintype) O-glycosylation in EMT process, induced with transforming growth factor β (TGF-β) in human prostate epithelial cell lines. We found that: (i) TGF-β treatment caused up-regulation of oncofetal fibronectin (onfFN), which is defined by mAb FDC6, and expressed in cancer or fetal cells/tissues, but not in normal adult cells/tissues. The reactivity of mAb FDC6 requires the addition of an O-glycan at a specific threonine, inside the type III homology connective segment (IIICS) domain of FN. (ii) This change is associated with typical EMT characteristics; i.e., change from epithelial to fibroblastic morphology, enhanced cell motility, decreased expression of a typical epithelial cell marker, E-cadherin, and enhanced expression of mesenchymal markers. (iii) TGF-β treatment up-regulated mRNA level of FN containing the IIICS domain and GalNAc-T activity for the IIICS domain peptide substrate containing the FDC6 onfFN epitope. (iv) Knockdown of GalNAc-T6 and T3 inhibited TGF-β-induced up-regulation of onfFN and EMT process. (v) Involvement of GSLs was not detectable with the EMT process in these cell lines. These findings indicate the important functional role of expression of onfFN, defined by sitespecific O-glycosylation at IIICS domain, in the EMT process.O-glycosylated fibronectin | siRNA G lycoconjugates, such as glycosphingolipids (GSLs) and N-and O-linked glycoproteins, have been shown to play important roles in embryogenesis (1), tumorigenesis, and cancer progression (2). Specific types of glycosyl residues modulate particular signaling pathways and regulate cell phenotypes. For example, GM3 inhibits epithelial growth factor receptor (EGFR) activation (3, 4); GM2 associated with tetraspanine CD82 inhibits the activation of the hepatocyte growth factor receptor cMet (5); and O-Fucose glycans modulate Notch signaling, which controls the fate of many cell types (6-8).Epithelial-mesenchymal transition (EMT) was initially observed during early embryonic development and organ formation (9-11). Accumulating evidence has shown that the EMT process plays a key role in disease development, particularly in cancer progression to metastasis (10-14) and fibrosis (15). During EMT, cells lose their apical-basal polarity, change morphology to fibroblastic, display reduced expression of epithelial cell marker molecules such as E-cadherin (Ecad), and enhance expression of mesenchymal cell marker molecules such as fibronectin (FN), N-cadherin (Ncad), vimentin, and matrix-metalloproteinases (MMPs). When combined, these effects result in increased cell motility (10-15).Our recent studies found a reduction in specific GSLs (Gg4 and/ or GM2) in ...

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Section: Discussionsupporting

confidence: 94%

Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process

Freire-de-Lima

Gelfenbeyn

Ding

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

130

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“…Twist1 was previously suggested as a good candidate for targeted therapy of prostate cancer patients. 14 Our findings further support this approach and suggest that targeting mutp53 may deplete Twist1 levels and reduce the invasiveness of cancer cells.…”

Section: Discussionsupporting

confidence: 75%

“…12 In prostate cancer, strong Twist1 expression is increased by mutant p53 I Kogan-Sakin et al nuclear Twist1 staining correlates with high Gleason score and metastasis. 13,14 Thus, we decided to investigate whether a molecular cross-talk exists between mutp53 and Twist1 expression in M cells. Interestingly, Twist1 upregulation was initially evident at passage 40, which is 15 passages after p53 R175H was introduced to the cells.…”

Section: Resultsmentioning

confidence: 99%

Mutant p53R175H upregulates Twist1 expression and promotes epithelial–mesenchymal transition in immortalized prostate cells

et al. 2010

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A mutation within one allele of the p53 tumor suppressor gene can inactivate the remaining wild-type allele in a dominantnegative manner and in some cases can exert an additional oncogenic activity, known as mutant p53 'gain of function' (GOF). To study the role of p53 mutations in prostate cancer and to discriminate between the dominant-negative effect and the GOF activity of mutant p53, we measured, using microarrays, the expression profiles of three immortalized prostate epithelial cultures expressing wild-type, inactivated p53 or mutated p53. Analysis of these gene expression profiles showed that both inactivated p53 and p53 R175H mutant expression resulted in the upregulation of cell cycle progression genes. A second group, which was upregulated exclusively by mutant p53 R175H , was predominantly enriched in developmental genes. This group of genes included the Twist1, a regulator of metastasis and epithelial-mesenchymal transition (EMT). Twist1 levels were also elevated in metastatic prostate cancer-derived cell line DU145, in immortalized lung fibroblasts and in a subset of lung cancer samples, all in a mutant p53-dependent manner. p53 R175H mutant bearing immortalized epithelial cells showed typical features of EMT, such as higher expression of mesenchymal markers, lower expression of epithelial markers and enhanced invasive properties in vitro. The mechanism by which p53 R175H mutant induces Twist1 expression involves alleviation of the epigenetic repression. Our data suggest that Twist1 expression might be upregulated following p53 mutation in cancer cells.

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“…Creemos que es necesario complementar este estudio con un marcaje adecuado de la microdensidad vascular, así como de las proteínas que se ven alteradas cuando las células malignas epiteliales adoptan un fenotipo mesenquimático que las hace capaces de desprenderse del epitelio, atravesar la lámina basal y migrar, degradando la matriz y modificando su citoesqueleto de modo de hacerse móviles permitiendo la generación de metástasis a distancia 12 . Sería interesante en estos pacientes estudiar el patrón de expresión de Ecadherina, beta-cateninas, vimentina, TWIST u otras proteínas que pudieran modificarse 6,26 .…”

Section: Discussionunclassified

“…Uno de los potenciales factores pronósticos que se está estudiando ampliamente es el factor de crecimiento vascular endotelial (VEGF), por su relación, no sólo con la angiogénesis tumoral, sino también con otros fenómenos descritos más recientemente, como la transición epitelio-mesenquimática (EMT), inhibición de la apoptosis, capacidad migratoria de las células, capacidad adhesiva a la matriz y proliferación de las células tumorales por vías autocrinas y paracrinas [6][7][8][9][10][11][12][13] . El concepto de EMT en oncología es relativamente nuevo y podría reflejar un proceso de transdiferenciación en vez de un proceso de desdiferenciación 15 .…”

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Identificación de factor de crecimiento vascular endotelial en células glandulares de tejido prostético maligno y benigno: Relación con la recidiva tumoral al año de la prostatectomía

Acuña¹,

Ellwanger

Ramírez

et al. 2013

Rev. méd. Chile

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The epithelial-mesenchymal transition-inducing factor TWIST is an attractive target in advanced and/or metastatic bladder and prostate cancers

Cited by 96 publications

References 46 publications

Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process

Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process

Mutant p53R175H upregulates Twist1 expression and promotes epithelial–mesenchymal transition in immortalized prostate cells

Identificación de factor de crecimiento vascular endotelial en células glandulares de tejido prostético maligno y benigno: Relación con la recidiva tumoral al año de la prostatectomía

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