1. Expression of asporin and other extracellular matrix related proteins (CTHRC1, POSTN, LRRC15, CSPG2) will be analysed after modulation of TGF beta and Wnt signaling pathways. 2. Importance of asporin in invasive growth will be studied after its knock-down with siRNA/shRNA and modulation of TGF beta and Wnt pathways by adhesion, migration and invasive tests. 3. Expression of asporin and other selected protein will be evaluated in archive specimens with invasive breast and prostate cancer. 4. The obtained data will contribute to elucidating the role of asporin in breast and prostate cancer and can bring important therapeutic implications for treatment of these cancers.

1. Exprese asporinu a dalších proteinů extracelulární matrix (CTHRC1, POSTN, LRRC15, CSPG2) bude sledována po modulaci signálních drah TGF beta a Wnt. 2. Význam asporinu pro invazivní růst bude studován po knock-down pomocí siRNA/shRNA a po modulaci signálních drah TGF beta a Wnt v adhezivních, migračních a invazivních testech. 3. Exprese asporinu a dalších vybraných genů bude stanovena u pacientů s invazivními karcinomy prsu a prostaty. 4. Získané výsledky přispějí k objasnění úlohy asporinu v karcinomech prsu a prostaty a mohou vést k identifikaci nových terapeutických postupů u těchto závažných onemocnění.

• MeSH
• buněčná adheze MeSH
• extracelulární matrix - proteiny MeSH
• inhibice migrace buněk MeSH
• invazivní růst nádoru MeSH
• nádory prostaty MeSH
• nádory prsu MeSH
• proteiny Wnt MeSH
• proteoglykany MeSH
• transformující růstový faktor beta MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• biologie
• onkologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

Deregulation of expression and function of cytokines belonging to the transforming growth factor-β (TGF-β) family is often associated with various pathologies. For example, this cytokine family has been considered a promising target for cancer therapy. However, the detailed functions of several cytokines from the TGF-β family that could have a role in cancer progression and therapy remain unclear. One of these molecules is growth/differentiation factor-15 (GDF-15), a divergent member of the TGF-β family. This stress-induced cytokine has been proposed to possess immunomodulatory functions and its high expression is often associated with cancer progression, including prostate cancer (PCa). However, studies clearly demonstrating the mechanisms for signal transduction and functions in cell interaction, cancer progression and therapy are still lacking. New GDF-15 roles have recently been identified for modulating osteoclast differentiation and for therapy for PCa bone metastases. Moreover, GDF-15 is as an abundant cytokine in seminal plasma with immunosuppressive properties. We discuss studies that focus on the regulation of GDF-15 expression and its role in tissue homeostasis, repair and the immune response with an emphasis on the role in PCa development.

• MeSH
• buněčná diferenciace MeSH
• cílená molekulární terapie MeSH
• imunosupresivní léčba MeSH
• lidé MeSH
• nádory kostí * genetika   metabolismus   sekundární   MeSH
• nádory prostaty * genetika   metabolismus   MeSH
• osteoklasty cytologie   metabolismus   MeSH
• růstový diferenciační faktor 15 * genetika   metabolismus   MeSH
• signální transdukce MeSH
• transformující růstový faktor beta metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: Steroid receptor coactivators p300 and CBP are highly expressed in advanced prostate cancer. They potentiate activation of androgen receptor by androgens and anti-androgens. In the present study, we have addressed the question whether these coactivators enhance activity of estrogen receptor-beta (ER-β), which is variably expressed in prostate cancers. METHODS: Expression levels of the coactivators p300 and CBP were manipulated by plasmid or siRNA transfections and activity of ER-β was measured by luciferase assays. Viability was measured by MTT assays and cellular migration was determined by wound-healing and Boyden chamber assays. RESULTS: High expression of ER-β was found in PC3 cells which were used for the experiments. p300 or CBP enhanced activation of ER-β by genistein. Antiestrogens did not acquire agonistic properties in the presence of increased concentrations of either coactivator. Inhibition of p300 or CBP decreased genistein stimulation of ER-β. Genistein reduced migration of PC3 prostate cancer cells and down-regulation of p300 potentiated this effect. CONCLUSIONS: p300 and CBP are implicated in regulation of ER-β activity and cellular migration in prostate cancer. These findings are important for understanding of action of ER-β in carcinoma of the prostate.

• MeSH
• beta receptor estrogenů genetika   fyziologie   MeSH
• genistein farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty patologie   MeSH
• pohyb buněk účinky léků   MeSH
• protein p300 asociovaný s E1A fyziologie   MeSH
• protein vázající CREB fyziologie   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• exprese genu účinky léků   MeSH
• financování organizované MeSH
• nádorové buněčné linie cytologie   účinky léků   MeSH
• nádory prsu MeSH
• proteoglykany farmakologie   MeSH
• techniky in vitro MeSH
• Publikační typ
• abstrakt z konference MeSH

Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT), a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated β-galactosidase activity, heterochromatin protein 1β foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate cancer cells was under separate control. These data demonstrate a previously unrecognized link between inhibition of androgen receptor signaling, down-regulation of S-phase kinase-associated protein 2, and the appearance of secretory, tumor-promoting senescent cells in prostate tumors. We propose that ADT may contribute to the development of androgen-independent prostate cancer through modulation of the tissue microenvironment by senescent cells.

• MeSH
• androgenní receptory metabolismus   MeSH
• antagonisté androgenů farmakologie   MeSH
• beta-galaktosidasa metabolismus   MeSH
• down regulace účinky léků   MeSH
• fosfohydroláza PTEN metabolismus   MeSH
• IGFBP-3 metabolismus   MeSH
• kathepsin B metabolismus   MeSH
• konfokální mikroskopie MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty genetika   metabolismus   patologie   MeSH
• proteiny asociované s kinázou S-fáze genetika   metabolismus   MeSH
• průtoková cytometrie MeSH
• RNA interference MeSH
• signální transdukce účinky léků   MeSH
• stárnutí buněk účinky léků   MeSH
• vimentin metabolismus   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Collagen triple helix repeat containing 1 (CTHRC1) affects Wnt signalling, collagen deposition and bone formation. It is an extracellular matrix protein which is also abnormally expressed in the tumour microenvironment. CTHRC1 has not been studied in breast cancer by immunohistochemistry. AIMS: To examine expression of CTHRC1 together with periostin and versican in breast cancer patients and investigate its association with clinicopathological characteristics. METHODS: The formalin-fixed paraffin-embedded tissues of 173 invasive carcinomas (classified into WHO histotypes and luminal, triple negative and Her2 subtypes), as well as normal tissues, precursor lesions and metastatic lymph nodes were stained by relevant antibodies, assessed semiquantitatively by histoscore and statistically evaluated. RESULTS: Expression of CTHRC1, versican and periostin was significantly higher in breast cancer than in normal tissue or precursor lesions. CTHRC1 stromal expression was enhanced in triple negative cases and also in patients with bone metastasis. Periostin expression was high in primary tumours, in particular triple negative ones, and also in their lymph node metastases. Cox regression analysis showed that in patients with high periostin, the risk of bone metastases increased with increased CTHRC1 expression. CONCLUSIONS: CTHRC1 and periostin play important roles in breast cancer progression. These preliminary results show that combined evaluation of CTHRC1 and periostin could serve as a potential marker for breast cancer bone metastasis; the other observations contribute to the description of the tumour microenvironment, with implications for lymph node and bone metastasis.

• MeSH
• dospělí MeSH
• extracelulární matrix - proteiny metabolismus   MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfatické metastázy MeSH
• molekuly buněčné adheze metabolismus   MeSH
• nádorové biomarkery metabolismus   MeSH
• nádory kostí metabolismus   sekundární   MeSH
• nádory prsu metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• versikany metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Background. The Wnt signaling pathway is crucial for cell fate decisions, stem cell renewal, regulation of cell proliferation and differentiation. Deregulated Wnt signaling is also implicated in a number of hereditary and degenerative diseases and cancer. Methods and results. This review highlights the role of the Wnt pathway in the regulation of stem/progenitor cell renewal and prostate gland development and how this signaling is altered in prostate cancer. Recent evidence suggests that Wnt signaling regulates androgen activity in prostate cancer cells, enhances androgen receptor expression and promotes the growth of prostate cancer even after androgen ablation therapy. There is also strong evidence that Wnt signaling is enhanced in androgen-ablation resistant tumors and bone metastases. Conclusions. Further study of the modulators of this pathway will be of therapeutic relevance as inhibition of Wnt signaling may have the potential to reduce the self-renewal and aggressive behaviour of prostate cancer while Wnt signaling activation might enhance stem cell activity when tissue regeneration is required.

• MeSH
• financování organizované MeSH
• kmenové buňky MeSH
• lidé MeSH
• nádory prostaty metabolismus   patofyziologie   MeSH
• prostata růst a vývoj   MeSH
• proteiny Wnt fyziologie   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

• Publikační typ
• abstrakt z konference MeSH

BACKGROUND: Epithelial-mesenchymal transition (EMT) underlying cancer cell invasion and metastasis has been thoroughly studied in prostate cancer. Although EMT markers have been clinically observed in benign prostate hyperplasia, molecular events underlying the onset and progression of EMT in benign prostate cells have not been described. METHODS: EMT in BPH-1 cells was induced by TGF-β1 treatment and the kinetics of expression of EMT markers, regulators, and selected miRNAs was assessed by western blotting and quantitative RT-PCR. RESULTS: EMT in BPH-1 cells was accompanied by rapid up-regulation of SNAI2/Slug and ZEB1 transcription factors, while changes in expression levels of ZEB2 and miR-200 family members were observed after extended time intervals. Invasive phenotype with EMT hallmarks, characterizing tumorigenic clones derived from BPH-1 cells, was associated with increased mRNA levels of SNAI2, ZEB1, and ZEB2, but was not associated with significant changes in basal levels of miR-200 family members. RNA interference revealed that SNAI2/Slug is crucial for TGF-β1-induced vimentin up-regulation and migration of BPH-1 cells. CONCLUSIONS: This study suggests that in BPH-1 cells the transcription factor SNAI2/Slug is important for EMT initiation, while the ZEB family of transcription factors in cooperation with the miR-200 family may oppose the reversal of the EMT phenotype.

• MeSH
• biologické markery metabolismus   MeSH
• buněčné linie MeSH
• epitelo-mezenchymální tranzice genetika   MeSH
• fenotyp MeSH
• homeodoménové proteiny genetika   MeSH
• hyperplazie prostaty patofyziologie   MeSH
• invazivní růst nádoru genetika   MeSH
• kinetika MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• mikro RNA metabolismus   MeSH
• pohyb buněk MeSH
• represorové proteiny genetika   MeSH
• transformující růstový faktor beta1 farmakologie   MeSH
• transkripční faktory biosyntéza   genetika   MeSH
• upregulace účinky léků   MeSH
• vimentin metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Publikační typ
• abstrakt z konference MeSH