Aristolochic acids (AAs) are a group of naturally occurring compounds present in many plant species of the Aristolochiaceae family. Exposure to AA is a significant risk factor for severe nephropathy, and urological and hepatobiliary cancers (among others) that are often recurrent and characterized by the prominent mutational fingerprint of AA. However, herbal medicinal products that contain AA continue to be manufactured and marketed worldwide with inadequate regulation, and possible environmental exposure routes receive little attention. As the trade of food and dietary supplements becomes increasingly globalized, we propose that further inaction on curtailing AA exposure will have far-reaching negative effects on the disease trends of AA-associated cancers. Our Review aims to systematically present the historical and current evidence for the mutagenicity and carcinogenicity of AA, and the effect of removing sources of AA exposure on cancer incidence trends. We discuss the persisting challenges of assessing the scale of AA-related carcinogenicity, and the obstacles that must be overcome in curbing AA exposure and preventing associated cancers. Overall, this Review aims to strengthen the case for the implementation of prevention measures against AA's multifaceted, detrimental and potentially fully preventable effects on human cancer development.
- MeSH
- kyseliny aristolochové * toxicita MeSH
- lidé MeSH
- mutageneze MeSH
- nádory * chemicky indukované epidemiologie MeSH
- veřejné zdravotnictví MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Smarca5, an ATPase of the ISWI class of chromatin remodelers, is a key regulator of chromatin structure, cell cycle and DNA repair. Smarca5 is deregulated in leukemia and breast, lung and gastric cancers. However, its role in oncogenesis is not well understood. Chromatin remodelers often play dosage-dependent roles in cancer. We therefore investigated the epigenomic and phenotypic impact of controlled stepwise attenuation of Smarca5 function in the context of primary cell transformation, a process relevant to tumor formation. Upon conditional single- or double-allele Smarca5 deletion, the cells underwent both accelerated growth arrest and senescence entry and displayed gradually increased sensitivity to genotoxic insults. These phenotypic characteristics were explained by specific remodeling of the chromatin structure and the transcriptome in primary cells prior to the immortalization onset. These molecular programs implicated Smarca5 requirement in DNA damage repair, telomere maintenance, cell cycle progression and in restricting apoptosis and cellular senescence. Consistent with the molecular programs, we demonstrate for the first time that Smarca5-deficient primary cells exhibit dramatically decreased capacity to bypass senescence and immortalize, an indispensable step during cell transformation and cancer development. Thus, Smarca5 plays a crucial role in key homeostatic processes and sustains cancer-promoting molecular programs and cellular phenotypes.
MicroRNAs are considered as promising prognostic and diagnostic biomarkers of human cancer since their profiles differ between tumor types. Most of the tumor profiling studies were performed on rarely available fresh frozen (FF) samples. Alternatively, archived formalin-fixed paraffin-embedded (FFPE) tissue samples are also well applicable to larger-scale retrospective miRNA profiling studies. The aim of this study was to perform systematic comparison of the miRNA expression profiles between FF and macrodissected FFPE tonsillar tumors using the TaqMan Low Density Array system, with the data processed by different software programs and two types of normalization methods. We observed a marked correlation between the miRNA expression profiles of paired FF and FFPE samples; however, only 27-38% of the differentially deregulated miRNAs overlapped between the two source systems. The comparison of the results with regard to the distinct modes of data normalization revealed an overlap in 58-67% of differentially expressed miRNAs, with no influence of the choice of software platform. Our study highlights the fact that for an accurate comparison of the miRNA expression profiles from published studies, it is important to use the same type of clinical material and to test and select the best-performing normalization method for data analysis.
- MeSH
- analýza hlavních komponent MeSH
- fixace tkání MeSH
- fixativa MeSH
- formaldehyd MeSH
- krční mandle metabolismus MeSH
- kryoprezervace * MeSH
- lidé MeSH
- mikro RNA metabolismus MeSH
- mikročipová analýza MeSH
- počítačové zpracování signálu MeSH
- software MeSH
- stanovení celkové genové exprese MeSH
- tonzilární nádory metabolismus MeSH
- zalévání tkání do parafínu * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Ocular lens morphogenesis is a model for investigating mechanisms of cellular differentiation, spatial and temporal gene expression control, and chromatin regulation. Brg1 (Smarca4) and Snf2h (Smarca5) are catalytic subunits of distinct ATP-dependent chromatin remodeling complexes implicated in transcriptional regulation. Previous studies have shown that Brg1 regulates both lens fiber cell differentiation and organized degradation of their nuclei (denucleation). Here, we employed a conditional Snf2h(flox) mouse model to probe the cellular and molecular mechanisms of lens formation. Depletion of Snf2h induces premature and expanded differentiation of lens precursor cells forming the lens vesicle, implicating Snf2h as a key regulator of lens vesicle polarity through spatial control of Prox1, Jag1, p27(Kip1) (Cdkn1b) and p57(Kip2) (Cdkn1c) gene expression. The abnormal Snf2h(-/-) fiber cells also retain their nuclei. RNA profiling of Snf2h(-/) (-) and Brg1(-/-) eyes revealed differences in multiple transcripts, including prominent downregulation of those encoding Hsf4 and DNase IIβ, which are implicated in the denucleation process. In summary, our data suggest that Snf2h is essential for the establishment of lens vesicle polarity, partitioning of prospective lens epithelial and fiber cell compartments, lens fiber cell differentiation, and lens fiber cell nuclear degradation.
- MeSH
- adenosintrifosfatasy metabolismus MeSH
- autofagie MeSH
- biologické modely MeSH
- buněčná diferenciace * MeSH
- buněčné jádro metabolismus MeSH
- buněčný cyklus MeSH
- chromozomální proteiny, nehistonové metabolismus MeSH
- DNA vazebné proteiny metabolismus MeSH
- DNA-helikasy metabolismus MeSH
- embryo savčí metabolismus MeSH
- epitelové buňky cytologie metabolismus MeSH
- jaderné proteiny metabolismus MeSH
- kompartmentace buňky MeSH
- mitofagie MeSH
- mutace genetika MeSH
- myši knockoutované MeSH
- oční čočka cytologie embryologie MeSH
- restrukturace chromatinu * MeSH
- transkripční faktor PAX6 metabolismus MeSH
- transkripční faktory metabolismus MeSH
- transkriptom genetika MeSH
- vývojová regulace genové exprese MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Better insights into the molecular changes involved in virus-associated and -independent head and neck cancer may advance our knowledge of HNC carcinogenesis and identify critical disease biomarkers. Here we aimed to characterize the expression profiles in a matched set of well-characterized HPV-dependent and HPV-independent tonsillar tumors and equivalent immortalized keratinocyte clones to define potential and clinically relevant biomarkers of HNC of different etiology. METHODS: Fresh frozen tonsillar cancer tissues were analyzed together with non-malignant tonsillar tissues and compared with cervical tumors and normal cervical tissues. Furthermore, relative miRNAs abundance levels of primary and immortalized human keratinocyte clones were evaluated. The global quantitation of miRNA gene abundance was performed using a TaqMan Low Density Array system. The confirmation of differentially expressed miRNAs was performed on a set of formalin-fixed paraffin-embedded tumor samples enriched for the tumor cell fraction by macrodissection. RESULTS: We defined 46 upregulated and 31 downregulated miRNAs characteristic for the HPV-positive tonsillar tumors and 42 upregulated miRNAs and 42 downregulated miRNAs characteristic for HPV-independent tumors. In comparison with the expression profiles in cervical tumors, we defined miR-141-3p, miR-15b-5p, miR-200a-3p, miR-302c-3p, and miR-9-5p as specific for HPV induced malignancies. MiR-335-5p, miR-579-3p, and miR-126-5p were shared by the expression profiles of HPV-positive tonsillar tumors and of the HPV immortalized keratinocyte clones, whereas miR-328-3p, miR-34c-3p, and miR-885-5p were shared by the miRNA profiles of HPV-negative tonsillar tumors and the HPV-negative keratinocytes. CONCLUSIONS: We identified the miRNAs characteristic for HPV-induced tumors and tonsillar tumors of different etiology, and the results were compared with those of the model system. Our report presents the basis for further investigations leading to the identification of clinically relevant diagnostic and/or therapeutic biomarkers for tumors of viral and non-viral etiology.
- MeSH
- analýza hlavních komponent MeSH
- genové regulační sítě MeSH
- infekce papilomavirem genetika MeSH
- keratinocyty cytologie patologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- mikro RNA genetika MeSH
- nádory děložního čípku genetika virologie MeSH
- regulace genové exprese u nádorů MeSH
- sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
- stanovení celkové genové exprese MeSH
- tonzilární nádory genetika virologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
The incidence of renal cell carcinoma (RCC) is increasing worldwide, and its prevalence is particularly high in some parts of Central Europe. Here we undertake whole-genome and transcriptome sequencing of clear cell RCC (ccRCC), the most common form of the disease, in patients from four different European countries with contrasting disease incidence to explore the underlying genomic architecture of RCC. Our findings support previous reports on frequent aberrations in the epigenetic machinery and PI3K/mTOR signalling, and uncover novel pathways and genes affected by recurrent mutations and abnormal transcriptome patterns including focal adhesion, components of extracellular matrix (ECM) and genes encoding FAT cadherins. Furthermore, a large majority of patients from Romania have an unexpected high frequency of A:T>T:A transversions, consistent with exposure to aristolochic acid (AA). These results show that the processes underlying ccRCC tumorigenesis may vary in different populations and suggest that AA may be an important ccRCC carcinogen in Romania, a finding with major public health implications.
- MeSH
- dospělí MeSH
- fokální adheze metabolismus MeSH
- fosfatidylinositol-3-kinasy genetika MeSH
- fúzní onkogenní proteiny genetika MeSH
- genetická variace * MeSH
- genom lidský genetika MeSH
- genomika * MeSH
- karcinom z renálních buněk genetika MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- mutační rychlost MeSH
- regulace genové exprese u nádorů MeSH
- sekvenční analýza DNA MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sestřih RNA genetika MeSH
- signální transdukce genetika MeSH
- stanovení celkové genové exprese 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
- Geografické názvy
- Evropa MeSH
The oncogenic cluster miR-17-92 encodes seven related microRNAs that regulate cell proliferation, apoptosis and development. Expression of miR-17-92 cluster is decreased upon cell differentiation. Here, we report a novel mechanism of the regulation of miR-17-92 cluster. Using transgenic PU.1(-/-) myeloid progenitors we show that upon macrophage differentiation, the transcription factor PU.1 induces the secondary determinant Egr2 which, in turn, directly represses miR-17-92 expression by recruiting histone demethylase Jarid1b leading to histone H3 lysine K4 demethylation within the CpG island at the miR-17-92 promoter. Conversely, Egr2 itself is targeted by miR-17-92, indicating existence of mutual regulatory relationship between miR-17-92 and Egr2. Furthermore, restoring EGR2 levels in primary acute myeloid leukaemia blasts expressing elevated levels of miR-17-92 and low levels of PU.1 and EGR2 leads to downregulation of miR-17-92 and restored expression of its targets p21CIP1 and BIM. We propose that upon macrophage differentiation PU.1 represses the miR-17-92 cluster promoter by an Egr-2/Jarid1b-mediated H3K4 demethylation mechanism whose deregulation may contribute to leukaemic states.
- MeSH
- biologické modely MeSH
- buněčná diferenciace genetika MeSH
- buňky NIH 3T3 MeSH
- epigeneze genetická fyziologie MeSH
- HL-60 buňky MeSH
- jaderné proteiny metabolismus fyziologie MeSH
- Jumonjiho doména s histondemethylasami metabolismus fyziologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- makrofágy metabolismus fyziologie MeSH
- mikro RNA genetika metabolismus MeSH
- multigenová rodina genetika MeSH
- myši MeSH
- protein 2 časné růstové odpovědi metabolismus fyziologie MeSH
- protoonkogenní proteiny genetika metabolismus fyziologie MeSH
- represorové proteiny metabolismus fyziologie MeSH
- sekvence nukleotidů MeSH
- sekvenční homologie nukleových kyselin MeSH
- technika přenosu genů MeSH
- trans-aktivátory genetika metabolismus fyziologie MeSH
- transfekce MeSH
- umlčování genů fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
The authors tested the diagnostic potential of the portable autofluorescence optical system that was developed in the preoperative evaluation of resection margins, and thus of the resection line safety in patients with low-positioned colorectal carcinoma. A total of 217 spectral measurements of the fluorescence properties of normal (117) and malignant (100) tissues in 19 patients with colorectal carcinoma were accomplished. The measured spectra thus acquired were then evaluated using logistic regression. Using the principal component method, the authors selected the 30 and 40 most significant wavelengths, respectively, which they then used to construct the logistic model. The model met the basic criteria of statistical significance. The classification power of the model was 79.7% (for 30 wavelengths) and 82.5% (for 40). Statistical discrimination was 0.88 and 0.91, respectively. These results confirm that the optical setup that we selected is suitable for the peroperative testing of the distal resection line. It is capable of differentiating with 90% confidence pathological tissue and thus of reliably guiding further histological processing.
- MeSH
- biopsie přístrojové vybavení metody statistika a číselné údaje MeSH
- fluorescence MeSH
- fluorescenční spektrometrie MeSH
- kolorektální nádory diagnóza chirurgie MeSH
- lidé středního věku MeSH
- lidé MeSH
- optická vlákna MeSH
- optické jevy MeSH
- optické prostředky MeSH
- peroperační doba MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- MeSH
- chronická lymfatická leukemie genetika patofyziologie MeSH
- lidé MeSH
- mikro RNA diagnostické užití genetika MeSH
- onkogenní proteiny v-myb diagnostické užití genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
