D-type cyclins are involved in cell cycle regulation and play an important role in the pathogenesis of lymphomas. Aberrant expression of cyclin D1 is associated with mantle cell lymphoma (MCL) and serves as a diagnostic marker of MCL. Analysis of cyclin D expression in tumor tissues of patients with diffuse large B-cell lymphoma (DLBCL) which comprises a heterogeneous group of tumors may contribute to their stratification. We analyzed expression of cyclin D1, D2, and D3 mRNAs in 30 MCL and 104 DLBCL patients using qRT-PCR and addressed their significance for disease outcome. We confirmed a high level of cyclin D1 mRNA in 29 MCL cases (97%). One case (3%) was identified as positive for cyclin D2. Expression of cyclin D1 was limited to MCL and did not occur in DLBCL. Overexpression of cyclin D2, which is rare in MCL, occurred more frequently in DLBCL (11 cases, 10.6%). We showed that high expression of cyclin D2 in DLBCL cases de novo decreased the overall survival rate (P=0.016) and progression-free survival (P=0.009). The expression pattern of cyclin D3 was similar in both types of studied lymphomas and it did not affect the disease outcome.
- MeSH
- cyklin D genetika metabolismus MeSH
- difúzní velkobuněčný B-lymfom metabolismus mortalita MeSH
- exprese genu MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfom z plášťových buněk metabolismus mortalita MeSH
- nádorové biomarkery genetika metabolismus MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři 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
BACKGROUND AND PURPOSE: Paulownia tomentosa is a rich source of geranylated flavanones, some of which we have previously shown to have cytotoxic activity. To identify members of this class of compounds with cytostatic effects, we assessed the effects of the geranylated flavanone tomentodiplacone B (TOM B) on cell cycle progression and cell cycle regulatory pathways of THP-1 human monocytic leukaemia cells. EXPERIMENTAL APPROACH: Cell viability was measured by dye exclusion and proliferation by WST-1 assays; cell cycle was monitored by flow cytometry. Regulatory proteins were assessed by immunoprecipitation and kinase assays, and Western blotting. KEY RESULTS: Tomentodiplacone B had no effect during the first 24 h of cell growth at concentrations between 1 and 2.5 µM, but inhibited cell growth in a dose-dependent manner at concentrations of 5 µM or higher. Growth inhibition during the first 24 h of exposure to TOM B was not accompanied by cytotoxicity as cells were accumulated in G1 phase dose-dependently. This G1 phase accumulation was associated with down-regulation of cyclin-dependent kinase 2 activity and also protein levels of cyclins E1 and A2. However, key stress-related molecules (γ-H2AX, p53 and p21) were not induced, suggesting that TOM B acts by directly inhibiting the cyclin-dependent kinase 2 signalling pathway rather than initiating DNA damage or cellular stress. CONCLUSIONS AND IMPLICATIONS: Our study provides the first evidence that TOM B directly inhibits proliferation of human monocytic leukaemia cells, and thus is a potential anticancer agent, preventing leukaemia cells from progressing from G1 phase into DNA synthesis.
- MeSH
- akutní monocytární leukemie MeSH
- antikarcinogenní látky farmakologie MeSH
- cyklin D metabolismus MeSH
- cyklin-dependentní kinasa 2 antagonisté a inhibitory biosyntéza metabolismus MeSH
- cykliny metabolismus MeSH
- down regulace účinky léků MeSH
- flavanony farmakologie MeSH
- G1 fáze účinky léků MeSH
- lidé MeSH
- monocyty cytologie účinky léků metabolismus MeSH
- monoterpeny farmakologie MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- signální transdukce účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
