microRNA-155
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The transcription factor PU.1 and its inhibitory microRNA-155 (miR-155) are important regulators of B-cell differentiation. PU.1 downregulation coupled with oncogenic miR-155 upregulation has been reported in lymphoid malignancies; however, these data have not been studied across different subtypes in relation to clinical outcomes. We studied expression of miR-155 and PU.1 in the six most prevalent human B-cell lymphomas (n = 131) including aggressive (DLBCL, HL, MCL) and indolent (B-CLL/SLL, MZL, FL) types. Levels of miR-155 and PU.1 inversely correlated in DLBCL, B-CLL/SLL, and FL tumor tissues. In HL tissues, an exceptionally high level of miR-155 was found in patients with unfavorable responses to first-line therapy and those who had shorter survival times. PU.1 downregulation was noted in B-CLL/SLL samples positive for the adverse prognostic markers CD38 and ZAP-70. Upregulation of miR-155 and downregulation of PU.1 expression are integral aspects of lymphoma biology that could mark aggressive behavior of some, but not all, lymphoma types.
- MeSH
- antigeny CD38 metabolismus MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfom metabolismus mortalita MeSH
- mikro RNA biosyntéza MeSH
- nádorové biomarkery biosyntéza MeSH
- prevalence MeSH
- protein-tyrosinkináza ZAP-70 metabolismus MeSH
- protoonkogenní proteiny biosyntéza MeSH
- regulace genové exprese u nádorů * MeSH
- RNA nádorová biosyntéza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- trans-aktivátory biosyntéza MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
High-level leukemia cell expression of micro-RNA 155 (miR-155) is associated with more aggressive disease in patients with chronic lymphocytic leukemia (CLL), including those cases with a low-level expression of ζ-chain-associated protein of 70 kD. CLL with high-level miR-155 expressed lower levels of Src homology-2 domain-containing inositol 5-phosphatase 1 and were more responsive to B-cell receptor (BCR) ligation than CLL with low-level miR-155. Transfection with miR-155 enhanced responsiveness to BCR ligation, whereas transfection with a miR-155 inhibitor had the opposite effect. CLL in lymphoid tissue expressed higher levels of miR155HG than CLL in the blood of the same patient. Also, isolated CD5(bright)CXCR4(dim) cells, representing CLL that had been newly released from the microenvironment, expressed higher levels of miR-155 and were more responsive to BCR ligation than isolated CD5(dim)CXCR4(bright) cells of the same patient. Treatment of CLL or normal B cells with CD40-ligand or B-cell-activating factor upregulated miR-155 and enhanced sensitivity to BCR ligation, effects that could be blocked by inhibitors to miR-155. This study demonstrates that the sensitivity to BCR ligation can be enhanced by high-level expression of miR-155, which in turn can be induced by crosstalk within the tissue microenvironment, potentially contributing to its association with adverse clinical outcome in patients with CLL.
- MeSH
- antigeny CD5 genetika metabolismus MeSH
- chronická lymfatická leukemie genetika mortalita patologie MeSH
- dospělí MeSH
- fosfatasy genetika metabolismus MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- lidé středního věku MeSH
- lidé MeSH
- ligand CD40 genetika metabolismus MeSH
- messenger RNA genetika MeSH
- mikro RNA genetika MeSH
- míra přežití MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádorové mikroprostředí MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- prognóza MeSH
- protein-tyrosinkináza ZAP-70 genetika metabolismus MeSH
- průtoková cytometrie MeSH
- receptory antigenů B-buněk genetika metabolismus MeSH
- receptory CXCR4 genetika metabolismus MeSH
- regulace genové exprese u leukemie * MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- signální transdukce MeSH
- vápník metabolismus MeSH
- western blotting MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: MicroRNAs (miRs) represent a distinct class of posttranscriptional modulators of gene expression with remarkable stability in sera. Several miRs are oncogenic (oncomiRs) and are deregulated in the pathogenesis of breast cancer and function to inhibit tumor suppressors. Routine blood monitoring of these circulating tumor-derived products could be of significant benefit to the diagnosis and relapse detection of early-stage breast cancer (EBC) patients. METHODS: Aim of this project was to determine expression of miR-155, miR-19a, miR-181b, miR-24, relative to let-7a in sera of 63 patients with EBC and 21 healthy controls. Longitudinal multivariate data analysis was performed to stochastically model the serum levels of each of the oncomiRs during disease phases: from diagnosis, after surgery, and following chemo/radiotherapy. Moreover, this analysis was utilized to evaluate oncomiR levels in EBC patients subgrouped using current clinical prognostic factors including HER2, Ki-67, and grade III. RESULTS: EBC patients significantly over-express the oncomiRs at the time of diagnosis. Following surgical resection the serum levels of miR-155, miR-181b, and miR-24 significantly decreased (p = 1.89e-05, 5.41e-06, and 0.00638, respectively) whereas the miR-19a decreased significantly after the therapy (p = 0.00869). Furthermore, in case of high-risk patients serum levels of miR-155, miR-19a, miR-181b, and miR-24 are significantly more abundant in comparison to low-risk group (p = 0.026, 0.02567, 0.0250, and 0.00990) and show a decreasing trend upon therapy. CONCLUSIONS: OncomiRs are significantly more abundant in the sera of EBC patients compared to controls at diagnosis. Differences in oncomiR levels reflecting EBC risk were also observed. Testing the oncomiRs may be useful for diagnostic purpose and possibly also for relapse detection in follow-up studies of EBC.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA krev genetika MeSH
- nádorové biomarkery krev genetika MeSH
- nádory prsu diagnóza genetika terapie MeSH
- prognóza MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- stupeň nádoru MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Lichen sclerosus je chronické kožní zánětlivé onemocnění postihující děti i dospělé, převážně ženy. Nemoc vede k atrofii epidermis, fibróze a jizvení a je často provázená pruritem. Nejčastěji postihuje oblast anogenitální, kde často působí poruchy funkce a je spojeno se zvýšeným rizikem vzniku karcinomu kůže vulvy, může se však vyskytovat i v jiných lokalizacích. Patogeneze nemoci je nejasná. Uplatňují se různé faktory včetně genetické predispozice a lokální iritace. Nejčastěji se zvažuje autoimunitní charakter nemoci zprostředkované cytokiny Th1 buněk, provázené zvýšenou expresí microRNA-155 a tvorbou protilátek proti glykoproteinu 1 extracellulární matrix. Diagnóza je většinou klinická, biopsie zpravidla není nutná. Lékem volby jsou velmi silné lokální kortikosteroidy (clobetasol), u mužů je často kurativní cirkumcize. U rozsáhlejšího postižení je možná aplikace fototerapie (zejména UVA1, méně UVB311), výjimečně se uplatňuje systémová terapie metotrexátem a kortikoidy. Vzhledem k chronickému charakteru onemocnění a možnému vzniku malignity je vhodné dlouhodobé sledování nemocných.
Lichen sclerosus is a chronic inflammatory skin disease affecting children and adults, mostly women, leading to atrophy of the epidermis, fibrosis and scarring, often accompanied by pruritus. It most often affects the anogenital area, where it causes functional impairment and is associated with an increased risk of vulvar skin cancer, however it can also occur in other localizations. The pathogenesis of the disease is unclear. Various factors are considered, including genetic predisposition and local irritation. The autoimmune nature of the disease, mediated by Th1 cell cytokines, accompanied by the increased expression of microRNA-155 and the production of antibodies to extracellular matrix glycoprotein 1, is most commonly proposed. The diagnosis is usually clinical, biopsy is mostly not necessary. The treatment of choice are strong topical corticosteroids (clobetasol), circumcision is often curative in men. For more extensive skin involvement, application of phototherapy is possible (especially UVA1, less UVB311), rarely systemic therapy with methotrexate and corticosteroids is used. Due to the chronic nature of the disease and the possible development of malignancy, long-term follow-up of patients is recommended.
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : il., tab. ; 31 cm
Projekt translační hemato-onkologie zaměřený na identifikaci patogeneze leukemií. Studuje negativní regulační smyčku mezi mikroRNA miR-155 a transkripčním faktorem PU.1 a její poškození u CLL, DLBCL a AML. Projekt, jež je podpořen předběžnými výsledky, navrhuje testovat nový model biologické terapie těchto onemocnění postavený na manipulaci ekvilibria miR-155:PU.1. Projekt dále zahrnuje identifikaci biologicky relevantních biomárkerů ve vztahu k patogenezi, prognóze a chemosenzitivitě studovaných onemocnění.; Translational research in hemato-oncology focused on identification of leukemia pathogenesis. Human chronic lymphocytic leukemia (CLL), difuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML) are newly characterized by disrupted negative feedback loop between myelo-lymphoid transcription factor PU.1 and oncogenic microRNA miR-155. Restoration of PU.1 expression corrects the PU.1:miR-155 equilibrium and results in leukemia differentiation. We aim to use miR-155 blocking sequence (sponge) toidentify novel disease hallmarks and prognostic/therapeutic targets in CLL, DLBCL, and AML that associate with the disease state and with the leukemia/lymphoma differentiation.
- MeSH
- chromatin MeSH
- genetická transkripce MeSH
- hematopoéza MeSH
- leukemie diagnóza genetika patofyziologie MeSH
- mikro RNA MeSH
- mikročipová analýza MeSH
- regulace genové exprese u leukemie MeSH
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- angiologie
- biologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
MicroRNAs belong to a group of short non-coding RNA molecules that are involved in the regulation of gene expression at multiple levels. Their function was described two decades ago, and, since then, microRNAs have become a rapidly developing field of research. Their participation in the regulation of cellular processes, such as proliferation, apoptosis, cell growth, and migration, made microRNAs attractive for cancer research. Moreover, as a single microRNA can simultaneously target multiple molecules, microRNAs offer a unique advantage in regulating multiple cellular processes in different cell types. Many of these cell types are tumor cells and the cells of the immune system. One of the most studied microRNAs in the context of cancer and the immune system is miR-155. MiR-155 plays a role in modulating innate and adaptive immune mechanisms in distinct immune cell types. As such, miR-155 can be part of the communication between the tumor and immune cells and thus impact the process of tumor immunoediting. Several studies have already revealed its effect on antitumor immune responses, and the targeting of this molecule is increasingly implemented in cancer immunotherapy. In this review, we discuss the current knowledge of miR-155 in the regulation of antitumor immunity and the shaping of the tumor microenvironment, and the plausible implementation of miR-155 targeting in cancer therapy.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
