The transcription factor c-Myb is an oncoprotein promoting cell proliferation and survival when aberrantly activated/expressed, thus contributing to malignant transformation. Overexpression of c-Myb has been found in leukemias, breast, colon and adenoid cystic carcinoma. Recent studies revealed its expression also in osteosarcoma cell lines and suggested its functional importance during bone development. However, the relevance of c-Myb in control of osteosarcoma progression remains unknown. A retrospective clinical study was carried out to assess a relationship between c-Myb expression in archival osteosarcoma tissues and prognosis in a cohort of high-grade osteosarcoma patients. In addition, MYB was depleted in metastatic osteosarcoma cell lines SAOS-2 LM5 and 143B and their growth, chemosensitivity, migration and metastatic activity were determined. Immunohistochemical analysis revealed that high c-Myb expression was significantly associated with poor overall survival in the cohort and metastatic progression in young patients. Increased level of c-Myb was detected in metastatic osteosarcoma cell lines and its depletion suppressed their growth, colony-forming capacity, migration and chemoresistance in vitro in a cell line-dependent manner. MYB knock-out resulted in reduced metastatic activity of both SAOS-2 LM5 and 143B cell lines in immunodeficient mice. Transcriptomic analysis revealed the c-Myb-driven functional programs enriched for genes involved in the regulation of cell growth, stress response, cell adhesion and cell differentiation/morphogenesis. Wnt signaling pathway was identified as c-Myb target in osteosarcoma cells. Taken together, we identified c-Myb as a negative prognostic factor in osteosarcoma and showed its involvement in the regulation of osteosarcoma cell growth, chemosensitivity, migration and metastatic activity.

• MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory kostí * patologie   MeSH
• osteosarkom * patologie   MeSH
• pohyb buněk genetika   MeSH
• prognóza MeSH
• proliferace buněk MeSH
• regulace genové exprese u nádorů MeSH
• retrospektivní studie MeSH
• signální dráha Wnt MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The transcription factor c-Myb can be involved in the activation of many genes with protumorigenic function; however, its role in breast cancer (BC) development is still under discussion. c-Myb is considered as a tumor-promoting factor in the early phases of BC, on the other hand, its expression in BC patients relates to a good prognosis. Previously, we have shown that c-Myb controls the capacity of BC cells to form spontaneous lung metastasis. Reduced seeding of BC cells to the lungs is linked to high expression of c-Myb and a decline in expression of a specific set of inflammatory genes. Here, we unraveled a c-Myb-IL1α-NF-κB signaling axis that takes place in tumor cells. We report that an overexpression of c-Myb interfered with the activity of NF-κB in several BC cell lines. We identified IL1α to be essential for this interference since it was abrogated in the IL1α-deficient cells. Overexpression of IL1α, as well as addition of recombinant IL1α protein, activated NF-κB signaling and restored expression of the inflammatory signature genes suppressed by c-Myb. The endogenous levels of c-Myb negatively correlated with IL1α on both transcriptional and protein levels across BC cell lines. We concluded that inhibition of IL1α expression by c-Myb reduces NF-κB activity and disconnects the inflammatory circuit, a potentially targetable mechanism to mimic the antimetastatic effect of c-Myb with therapeutic perspective.

• MeSH
• epitelo-mezenchymální tranzice MeSH
• interleukin-1alfa metabolismus   MeSH
• lidé MeSH
• mediátory zánětu metabolismus   MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory prsu etiologie   metabolismus   patologie   MeSH
• NF-kappa B metabolismus   MeSH
• protoonkogenní proteiny c-myb metabolismus   MeSH
• sekvence aminokyselin MeSH
• signální transdukce * MeSH
• stres endoplazmatického retikula MeSH
• zánět genetika   metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Tumor-associated macrophages (TAMs) are prominent components of tumor stroma that promotes tumorigenesis. Many soluble factors participate in the deleterious cross-talk between TAMs and transformed cells; however mechanisms how tumors orchestrate their production remain relatively unexplored. c-Myb is a transcription factor recently described as a negative regulator of a specific immune signature involved in breast cancer (BC) metastasis. Here we studied whether c-Myb expression is associated with an increased presence of TAMs in human breast tumors. Tumors with high frequency of c-Myb-positive cells have lower density of CD68-positive macrophages. The negative association is reflected by inverse correlation between MYB and CD68/CD163 markers at the mRNA levels in evaluated cohorts of BC patients from public databases, which was found also within the molecular subtypes. In addition, we identified potential MYB-regulated TAMs recruiting factors that in combination with MYB and CD163 provided a valuable clinical multigene predictor for BC relapse. We propose that identified transcription program running in tumor cells with high MYB expression and preventing macrophage accumulation may open new venues towards TAMs targeting and BC therapy.

• MeSH
• antigeny diferenciační myelomonocytární metabolismus   MeSH
• CD antigeny metabolismus   MeSH
• datové soubory jako téma MeSH
• dospělí MeSH
• Kaplanův-Meierův odhad MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• makrofágy imunologie   metabolismus   MeSH
• nádorové mikroprostředí genetika   imunologie   MeSH
• nádory prsu genetika   imunologie   mortalita   patologie   MeSH
• prognóza MeSH
• proliferace buněk MeSH
• protoonkogenní proteiny c-myb metabolismus   MeSH
• prsy patologie   MeSH
• receptory buněčného povrchu metabolismus   MeSH
• regulace genové exprese u nádorů imunologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stanovení celkové genové exprese 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

Metastasis accounts for most of cancer-related deaths. Paracrine signaling between tumor cells and the stroma induces changes in the tumor microenvironment required for metastasis. Transcription factor c-Myb was associated with breast cancer (BC) progression but its role in metastasis remains unclear. Here we show that increased c-Myb expression in BC cells inhibits spontaneous lung metastasis through impaired tumor cell extravasation. On contrary, BC cells with increased lung metastatic capacity exhibited low c-Myb levels. We identified a specific inflammatory signature, including Ccl2 chemokine, that was expressed in lung metastatic cells but was suppressed in tumor cells with higher c-Myb levels. Tumor cell-derived Ccl2 expression facilitated lung metastasis and rescued trans-endothelial migration of c-Myb overexpressing cells. Clinical data show that the identified inflammatory signature, together with a MYB expression, predicts lung metastasis relapse in BC patients. These results demonstrate that the c-Myb-regulated transcriptional program in BCs results in a blunted inflammatory response and consequently suppresses lung metastasis.

• MeSH
• apoptóza MeSH
• chemokin CCL2 genetika   metabolismus   MeSH
• lidé MeSH
• lokální recidiva nádoru genetika   metabolismus   patologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádorové buňky kultivované MeSH
• nádorové mikroprostředí MeSH
• nádory plic genetika   metabolismus   sekundární   MeSH
• nádory prsu genetika   metabolismus   patologie   MeSH
• prognóza MeSH
• proliferace buněk MeSH
• protoonkogenní proteiny c-myb genetika   metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Wedelactone (WL), a plant polyphenolic derivative of coumestan, represents a promising anti-cancer agent. The underlying mechanisms of its action are not fully understood and appear to involve interplay with copper ions. Herein, we examined coordination and redox interactions of WL with Cu2+ in phosphate buffer (pH 7), and in two breast cancer cell lines. EPR, UV-Vis and fluorescence spectroscopy showed that WL and Cu2+ build a coordination complex with 2 : 1 stoichiometry and distorted tetrahedral geometry. WL showed strong fluorescence that was quenched by Cu2+. The sequestration of the intracellular copper pool with neocuproine led to a significant drop in the cytotoxic effects of WL, whereas the co-application of Cu2+ and WL and the formation of an extracellular complex suppressed both the cytotoxic effects of WL and copper loading. Fluorescence microscopy showed that WL is mainly localized in the cytosol and significantly less in the nuclei. WL fluorescence was stronger in cells pretreated with neocuproine, implying that the complex of WL and Cu2+ is formed inside the cells. WL caused a two-fold increase in the lysosomal level of copper as well as copper-dependent lysosome membrane permeabilization. On the other hand, the protective effects of overexpression of thioredoxin 1 imply that WL exerts the main oxidative impact inside the nucleus. The interactions of WL with copper may be essential for therapeutic performance and selectivity against cancer cells, taking into account that a number of cancer types, including breast cancer, exhibit increased intratumoral copper levels or altered copper distribution.

• MeSH
• apoptóza MeSH
• komplexní sloučeniny metabolismus   MeSH
• kumariny farmakologie   MeSH
• lidé MeSH
• měď metabolismus   MeSH
• nádorové buňky kultivované MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   MeSH
• protinádorové látky farmakologie   MeSH
• subcelulární frakce metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mnohočetný myelom je druhé nejčastější hematoonkologické onemocnění charakterizované klonální proliferací plazmatických buněk a produkcí monoklonálního imunoglobulinu. Jedná se o heterogenní onemocnění, avšak mnohé studie uvádějí, že dysregulace cyklinů D patří k sjednocujícím událostem v rané patogenezi mnohočetného myelomu. Téměř u všech pacientů s tímto onemocněním byla pozorována zvýšená exprese alespoň jednoho z cyklinů D, nicméně v mnoha případech je mechanizmus jejich zvýšené exprese neznámý. Kromě známých a dobře popsaných úloh cyklinů D v buněčném cyklu se ukazuje, že mají i jiné funkce, kterými mohou přispívat k progresi nádorových onemocnění. Cykliny D slouží také jako prognostický marker a ke klasifikaci podskupin mnohočetného myelomu. V tomto přehledovém článku se zaměřujeme na význam cyklinů D u mnohočetného myelomu.

Multiple myeloma is the second most common hematooncological disease characterized by clonal proliferation of plasma cells and monoclonal immunoglobulin production. It is a heterogenous disease; however, dysregulation of cyclins D seems to be an early unifying pathogenic event in multiple myeloma. In almost all patients, there is increased expression level of at least one of the cyclins D. Nevertheless, the mechanism of this increase is unknown in many cases. Next to well‐known roles of cyclins D in the cell cycle, they have many other functions contributing to tumor cell progression. Cyclins D are prognostic markers and are also used for subclassification of multiple myeloma. In this review, we focus on significance of cyclins D in multiple myeloma. Key words: multiple myeloma – cyclin D – pathogenesis – cell cycle regulation – TC groups This study was supported by scientific program of the Czech Ministry of Education, Youth and Sports MSM0021622434, Grant of the Ministry of Health NT14575, NT12130 and NT13190 and internal grant of Faculty of Medicine, Masaryk Univerzity MUNI/11/InGA17/2012. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers. Submitted: 12. 5. 2013 Accepted: 6. 6. 2013

• MeSH
• apoptóza MeSH
• buněčný cyklus * fyziologie   MeSH
• cyklin D * fyziologie   genetika   metabolismus   MeSH
• embryo savčí MeSH
• fosforylace MeSH
• hematopoéza MeSH
• lidé MeSH
• mnohočetný myelom * genetika   patologie   MeSH
• modely nemocí na zvířatech MeSH
• molekulární biologie klasifikace   MeSH
• myši MeSH
• oprava DNA genetika   MeSH
• proteiny tepelného šoku HSP70 MeSH
• regulace genové exprese u nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH