In cancer, the activating transcription factor 2 (ATF2) has pleiotropic functions in cellular responses to growth stimuli, damage, or inflammation. Due to only limited studies, the significance of ATF2 in colorectal cancer (CRC) is not well understood. We report that low ATF2 levels correlated with worse prognosis and tumor aggressiveness in CRC patients. NanoString gene expression and ChIP analysis confirmed trophoblast cell surface antigen 2 (TROP2) as a novel inhibitory ATF2 target gene. This inverse correlation was further observed in primary human tumor tissues. Immunostainings revealed that high intratumoral heterogeneity for ATF2 and TROP2 expression was sustained also in liver metastasis. Mechanistically, our in vitro data of CRISPR/Cas9-generated ATF2 knockout (KO) clones revealed that high TROP2 levels were critical for cell de-adhesion and increased cell migration without triggering EMT. TROP2 was enriched in filopodia and displaced Paxillin from adherens junctions. In vivo imaging, micro-computer tomography, and immunostainings verified that an ATF2KO/TROP2high status triggered tumor invasiveness in in vivo mouse and chicken xenograft models. In silico analysis provided direct support that ATF2low/TROP2high expression status defined high-risk CRC patients. Finally, our data demonstrate that ATF2 acts as a tumor suppressor by inhibiting the cancer driver TROP2. Therapeutic TROP2 targeting might prevent particularly the first steps in metastasis, i.e., the de-adhesion and invasion of colon cancer cells.

• Klíčová slova
• CAM model, De-adhesion, EMT, Intratumoral heterogeneity, Liver metastasis, Migration,
• MeSH
• antigeny nádorové * genetika   metabolismus   MeSH
• kolorektální nádory * genetika   patologie   MeSH
• lidé MeSH
• molekuly buněčné adheze genetika   metabolismus   MeSH
• myši MeSH
• nádorové buněčné linie metabolismus   MeSH
• proliferace buněk MeSH
• transkripční faktor ATF2 * genetika   metabolismus   MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny nádorové * MeSH
• ATF2 protein, human MeSH Prohlížeč
• molekuly buněčné adheze MeSH
• TACSTD2 protein, human MeSH Prohlížeč
• transkripční faktor ATF2 * MeSH

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing on six members of a Polish family diagnosed with CRC and identified a novel germline variant in the protein tyrosine kinase 7 (inactive) gene (PTK7, ENST00000230419, V354M). Targeted screening of the variant in 1705 familial CRC cases and 1674 healthy elderly individuals identified the variant in an additional familial CRC case. Introduction of this variant in HT-29 cells resulted in increased cell proliferation, migration, and invasion; it also caused down-regulation of CREB, p21 and p53 mRNA and protein levels, and increased AKT phosphorylation. These changes indicated inhibition of apoptosis pathways and activation of AKT signaling. Our study confirmed the oncogenic function of PTK7 and supported its role in genetic predisposition of familial CRC.

• Klíčová slova
• AKT signaling pathway, PTK7, colorectal cancer, familial cancer variant prioritization pipeline, familial cancers, germline variant,
• MeSH
• genetická predispozice k nemoci MeSH
• inhibitor p21 cyklin-dependentní kinasy genetika   MeSH
• invazivní růst nádoru genetika   MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• molekuly buněčné adheze genetika   metabolismus   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• onkogeny MeSH
• pohyb buněk genetika   MeSH
• proliferace buněk genetika   MeSH
• protein vázající cAMP responzivní element genetika   MeSH
• protoonkogenní proteiny c-akt genetika   MeSH
• rodina MeSH
• rodokmen MeSH
• sekvenování exomu metody   MeSH
• senioři MeSH
• tyrosinkinasové receptory genetika   metabolismus   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CDKN1A protein, human MeSH Prohlížeč
• CREB1 protein, human MeSH Prohlížeč
• inhibitor p21 cyklin-dependentní kinasy MeSH
• molekuly buněčné adheze MeSH
• nádorový supresorový protein p53 MeSH
• protein vázající cAMP responzivní element MeSH
• protoonkogenní proteiny c-akt MeSH
• PTK7 protein, human MeSH Prohlížeč
• tyrosinkinasové receptory MeSH

Mechanisms of right ventricular (RV) dysfunction in heart failure (HF) are poorly understood. RV response to volume overload (VO), a common contributing factor to HF, is rarely studied. The goal was to identify interventricular differences in response to chronic VO. Rats underwent aorto-caval fistula (ACF)/sham operation to induce VO. After 24 weeks, RV and left ventricular (LV) functions, gene expression and proteomics were studied. ACF led to biventricular dilatation, systolic dysfunction and hypertrophy affecting relatively more RV. Increased RV afterload contributed to larger RV stroke work increment compared to LV. Both ACF ventricles displayed upregulation of genes of myocardial stress and metabolism. Most proteins reacted to VO in a similar direction in both ventricles, yet the expression changes were more pronounced in RV (pslope: < 0.001). The most upregulated were extracellular matrix (POSTN, NRAP, TGM2, CKAP4), cell adhesion (NCAM, NRAP, XIRP2) and cytoskeletal proteins (FHL1, CSRP3) and enzymes of carbohydrate (PKM) or norepinephrine (MAOA) metabolism. Downregulated were MYH6 and FAO enzymes. Therefore, when exposed to identical VO, both ventricles display similar upregulation of stress and metabolic markers. Relatively larger response of ACF RV compared to the LV may be caused by concomitant pulmonary hypertension. No evidence supports RV chamber-specific regulation of protein expression in response to VO.

• MeSH
• extracelulární matrix - proteiny genetika   metabolismus   MeSH
• krysa rodu Rattus MeSH
• molekuly buněčné adheze genetika   metabolismus   MeSH
• myokard metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
• proteom genetika   metabolismus   MeSH
• pyruvátkinasa genetika   metabolismus   MeSH
• remodelace komor * MeSH
• srdeční komory metabolismus   patologie   patofyziologie   MeSH
• srdeční selhání metabolismus   patologie   patofyziologie   MeSH
• tepový objem MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• extracelulární matrix - proteiny MeSH
• molekuly buněčné adheze MeSH
• Pkm protein, rat MeSH Prohlížeč
• protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
• proteom MeSH
• pyruvátkinasa MeSH
• Tgm2 protein, rat MeSH Prohlížeč

INTRODUCTION: Epidermolysis bullosa (EB) describes a family of rare genetic blistering skin disorders. Various subtypes are clinically and genetically heterogeneous, and a lethal postpartum form of EB is the generalized severe junctional EB (gs-JEB). gs-JEB is mainly caused by premature termination codon (PTC) mutations in the skin anchor protein LAMB3 (laminin subunit beta-3) gene. The ribosome in majority of translational reads of LAMB3PTC mRNA aborts protein synthesis at the PTC signal, with production of a truncated, nonfunctional protein. This leaves an endogenous readthrough mechanism needed for production of functional full-length Lamb3 protein albeit at insufficient levels. Here, we report on the development of drugs targeting ribosomal protein L35 (rpL35), a ribosomal modifier for customized increase in production of full-length Lamb3 protein from a LAMB3PTC mRNA. METHODS: Molecular docking studies were employed to identify small molecules binding to human rpL35. Molecular determinants of small molecule binding to rpL35 were further characterized by titration of the protein with these ligands as monitored by nuclear magnetic resonance (NMR) spectroscopy in solution. Changes in NMR chemical shifts were used to map the docking sites for small molecules onto the 3D structure of the rpL35. RESULTS: Molecular docking studies identified 2 FDA-approved drugs, atazanavir and artesunate, as candidate small-molecule binders of rpL35. Molecular interaction studies predicted several binding clusters for both compounds scattered throughout the rpL35 structure. NMR titration studies identified the amino acids participating in the ligand interaction. Combining docking predictions for atazanavir and artesunate with rpL35 and NMR analysis of rpL35 ligand interaction, one binding cluster located near the N-terminus of rpL35 was identified. In this region, the nonidentical binding sites for atazanavir and artesunate overlap and are accessible when rpL35 is integrated in its natural ribosomal environment. CONCLUSION: Atazanavir and artesunate were identified as candidate compounds binding to ribosomal protein rpL35 and may now be tested for their potential to trigger a rpL35 ribosomal switch to increase production of full-length Lamb3 protein from a LAMB3PTC mRNA for targeted systemic therapy in treating gs-JEB.

• Klíčová slova
• Drug development, Epidermolysis bullosa, Premature termination codon, Ribosomal protein L35, Skin models, mutations,
• MeSH
• artesunát chemie   MeSH
• atazanavir sulfát chemie   MeSH
• epidermolysis bullosa junkční genetika   patologie   MeSH
• fyziologie kůže MeSH
• kalinin MeSH
• kůže patologie   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• molekuly buněčné adheze genetika   MeSH
• ribozomální proteiny metabolismus   MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• artesunát MeSH
• atazanavir sulfát MeSH
• messenger RNA MeSH
• molekuly buněčné adheze MeSH
• ribozomální proteiny MeSH

Biofilm formation is regarded as an important factor in the establishment of infections caused by Staphylococcus aureus. In the present study, phenotypic and molecular assays were used to evaluate antibiofilm potential of thiosemicarbazide (Tsc) conjugated with silver nanoparticles (Ag NPs) and functionalized by glutamic acid (Ag@Glu/Tsc NPs) against methicillin-resistant S. aureus (MRSA). Ag NPs were synthesized using precipitation method and conjugated to Tsc using glutamic acid. The NPs were characterized using SEM and FTIR spectroscopy analyses. Then, antibiofilm potential of the prepared NPs against MRSA strains was evaluated using phenotypic method and their effects on the expression of biofilm-associated genes icaA and icaD. Finally, the genes involved with the synthesis of intercellular adhesion molecules were determined. According to the results, Ag@Glu/Tsc NPs inhibited biofilm formation of MRSA strains up to 76.7% compared with the control. In addition, expression of the biofilm-associated genes icaA and icaD reduced by 66.7% and 60.3%, respectively in the presence of sub-inhibitory concentration of Ag@Glu/Tsc NPs. In conclusion, Ag@Glu/Tsc NPs could be considered as a potent antibacterial agent to inhibit bacterial biofilms.

• MeSH
• antibakteriální látky farmakologie   MeSH
• bakteriální geny genetika   MeSH
• biofilmy účinky léků   MeSH
• kovové nanočástice chemie   MeSH
• mikrobiální testy citlivosti MeSH
• molekuly buněčné adheze genetika   MeSH
• semikarbazidy farmakologie   MeSH
• Staphylococcus aureus účinky léků   genetika   MeSH
• stříbro farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• molekuly buněčné adheze MeSH
• semikarbazidy MeSH
• stříbro MeSH
• thiosemicarbazide MeSH Prohlížeč

Endometrial cells undergo very specific changes associated with reproductive processes. Cells prepare for embryo development by increasing their volume. Then, if fertilization fails, endometrial cells are liable for apoptosis, preparing new cells that are ready for subsequent processes related to the possibility of embryo implantation and the development of pregnancy. PTX3 and TNFAIP6 are absent or reduced in cultured COCs, resulting in a functional change in COC in vitro. In this work, we want to check how PTX3, HAS2 and TNFAIP6 behave in luminal epithelium primary cell culture. Cells obtained during slaughter from porcine specimens were cultured primarily in vitro for 7 days. Their proliferation patterns were then analysed using RTCA, with the expression of genes of interest evaluated with the use of immunofluorescence and RT-qPCR. The results of these changes in the expression of the genes of interest were analysed on each of the seven days of the porcine luminal primary cell culture. Our study showed the increased level of PTX3, HAS2 and TN¬FAIP6 expression at the same hours of primary culture. Rt-qPCR showed a higher level of expression of the PTX3 gene in the first 72 h, at the end of the lag phase (in the phase of stasis in which the cells adapt to the new environment and often die). In contrast, TNFAIP6 expression increases about 96 hours when the cells are in the full log phase (logarithmic phase growth) and continue this trend in the plateau phase. We did not observe such drastic changes in the HAS2 expression pattern, which leads us to hypothesize that PTX3 and TNFAIP6 are designed to maintain a constant level of HAS2 in the cell throughout its lifetime. The obtained results could become a point of reference for further in vivo and clinical research.

• Klíčová slova
• genes expression, luminal epithelial cells, pig, primary culture,
• MeSH
• C-reaktivní protein genetika   MeSH
• endometrium cytologie   MeSH
• epitelové buňky cytologie   MeSH
• hyaluronansynthasy genetika   MeSH
• molekuly buněčné adheze genetika   MeSH
• prasata MeSH
• primární buněčná kultura MeSH
• proliferace buněk MeSH
• sérový amyloidový protein genetika   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• C-reaktivní protein MeSH
• hyaluronansynthasy MeSH
• molekuly buněčné adheze MeSH
• PTX3 protein MeSH Prohlížeč
• sérový amyloidový protein MeSH

• MeSH
• adaptivní imunita MeSH
• akutní koronární syndrom krev   diagnóza   terapie   MeSH
• antigeny CD44 genetika   MeSH
• antikoagulancia terapeutické užití   MeSH
• aterosklerotický plát komplikace   MeSH
• biologické markery krev   MeSH
• časná diagnóza MeSH
• diagnostické techniky kardiovaskulární MeSH
• duální protidestičková léčba MeSH
• exprese genu MeSH
• GPI-vázané proteiny genetika   MeSH
• hodnocení rizik MeSH
• hyaluronoglukosaminidasa genetika   MeSH
• hypolipidemika terapeutické užití   MeSH
• infarkt myokardu klasifikace   diagnóza   terapie   MeSH
• koronární angioplastika metody   MeSH
• lidé MeSH
• magnetická rezonance kinematografická MeSH
• molekuly buněčné adheze genetika   MeSH
• oxygenoterapie MeSH
• přirozená imunita MeSH
• remodelace cév MeSH
• ruptura MeSH
• sexuální faktory MeSH
• srdce diagnostické zobrazování   MeSH
• statiny terapeutické užití   MeSH
• stenty MeSH
• takotsubo kardiomyopatie klasifikace   diagnóza   mortalita   MeSH
• transportní proteiny krev   MeSH
• troponin krev   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antigeny CD44 MeSH
• antikoagulancia MeSH
• biologické markery MeSH
• CD44 protein, human MeSH Prohlížeč
• GPI-vázané proteiny MeSH
• Hyal2 protein, human MeSH Prohlížeč
• hyaluronoglukosaminidasa MeSH
• hypolipidemika MeSH
• molekuly buněčné adheze MeSH
• myosin-binding protein C MeSH Prohlížeč
• statiny MeSH
• transportní proteiny MeSH
• troponin MeSH

Tumour necrosis factor-stimulated gene 6 (TSG6) is a protective inflammatory reaction gene which is upregulated by inflammatory processes. Recent studies suggest that TSG-6 exhibits anti-scarring effects. However, the mechanism of TSG-6 action in the scar formation remains poorly understood. We investigated whether TSG-6 affects growth of the human hypertrophic scar fibroblasts (HSFs) via Fas/FasL signalling pathway. Cultured HSFs were transfected with a vector carrying the TSG6 gene (pLVX-Puro-TSG-6) or with a vector not containing the TSG6 gene (pLVX-Puro). Untransfected HSFs served as a control group to both transfected HSFs. The expressions level of TSG-6 was up-regulated in the pLVX-Puro-TSG-6 group at the protein and mRNA level. MTT and flow cytometry were used to assess the effect of TSG-6 on the growth and apoptotic status of HSFs. Finally, qRT-PCR and western blot were used to measure the expression levels of Fas, FasL, FADD, caspase-3 and caspase-8 in each group. The apoptosis rate was significantly enhanced and the growth rate reduced in the HSFs transfected with the TSG6 gene vector. The expression levels of Fas, FasL, FADD, caspase-3 and caspase- 8 were significantly raised in the TSG-6 overexpressing HSFs. It is concluded that increased expression of TSG-6 may induce apoptosis of human hypertrophic scar fibroblasts via activation of the Fas/FasL signalling pathway.

• MeSH
• antigeny CD95 metabolismus   MeSH
• apoptóza * MeSH
• dítě MeSH
• dospělí MeSH
• fibroblasty patologie   MeSH
• jizva hypertrofická genetika   patologie   MeSH
• lidé MeSH
• ligand Fas metabolismus   MeSH
• messenger RNA genetika   metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• molekuly buněčné adheze genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• signální transdukce * MeSH
• viabilita buněk MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD95 MeSH
• FAS protein, human MeSH Prohlížeč
• FASLG protein, human MeSH Prohlížeč
• ligand Fas MeSH
• messenger RNA MeSH
• molekuly buněčné adheze MeSH
• TNFAIP6 protein, human MeSH Prohlížeč

The cell surface glycoprotein Trop-2 is commonly overexpressed in carcinomas and represents an exceptional antigen for targeted therapy. Here, we provide evidence that surface Trop-2 expression is functionally connected with an epithelial phenotype in breast and prostate cell lines and in patient tumor samples. We further show that Trop-2 expression is suppressed epigenetically or through the action of epithelial-to-mesenchymal transition transcription factors and that deregulation of Trop-2 expression is linked with cancer progression and poor patient prognosis. Moreover, our data suggest that the cancer plasticity-driven intratumoral heterogeneity in Trop-2 expression may significantly contribute to response and resistance to therapies targeting Trop-2-expressing cells.

• MeSH
• antigeny nádorové genetika   metabolismus   MeSH
• CD antigeny biosyntéza   MeSH
• epitelo-mezenchymální tranzice fyziologie   MeSH
• epitelové buňky metabolismus   MeSH
• kadheriny biosyntéza   MeSH
• karcinom patologie   MeSH
• lidé MeSH
• metylace DNA genetika   MeSH
• molekuly buněčné adheze genetika   metabolismus   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty mortalita   patologie   MeSH
• nádory prsu mortalita   patologie   MeSH
• progrese nemoci MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny nádorové MeSH
• CD antigeny MeSH
• CDH1 protein, human MeSH Prohlížeč
• kadheriny MeSH
• molekuly buněčné adheze MeSH
• TACSTD2 protein, human MeSH Prohlížeč

Glycan metabolism balance is critical for cell prosperity, and macromolecule glycosylation is essential for cell communication, signaling and survival. Thus, glycotherapy may be a potential cancer treatment. The aim of the present study was to determine whether combined synthetic glycoconjugates (GCs) induce changes in gene expression that alter the survival of colon cancer cells. The current study evaluated the effect of the GCs N‑acetyl‑D‑glucosamine modified polyamidoamine dendrimer and calix[4]arene scaffold on cancer cell proliferation, apoptosis, invasion and sensitivity to immune cell‑mediated killing. Using reverse transcription‑quantitative polymerase chain reaction, the expression of genes involved in the aforementioned processes was measured. It was determined that GCs reduce the expression of the glucosaminyltransferases Mgat3 and Mgat5 responsible for surface glycosylation and employed components of the Wnt signaling pathway Wnt2B and Wnt9B. In addition, the calix[4]arene‑based GC reduced cell colony formation; this was accompanied by the downregulation of the metalloproteinase Mmp3. By contrast, the dendrimer‑based GC affected the expression of the glucose transporter components Sglt1 and Egfr1. Therefore, to the best of our knowledge, the present study is the first to reveal that N‑acetyl‑D‑glucosamine‑dendrimer/calix[4]arene GCs alter mRNA expression in a comprehensive way, resulting in the reduced malignant phenotype of the colon cancer cell line HT‑29.

• Klíčová slova
• N-acetyl-glucosaminyl-transferase, WNT, colon cancer cell, glycosylation, polyamidoamine dendrimer, calix[4]arene,
• MeSH
• apoptóza genetika   MeSH
• buňky HT-29 MeSH
• glukosa metabolismus   MeSH
• glykokonjugáty farmakologie   MeSH
• lidé MeSH
• molekuly buněčné adheze genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   MeSH
• nádory tračníku genetika   metabolismus   MeSH
• proliferace buněk MeSH
• proteiny usnadňující transport glukosy genetika   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• stanovení celkové genové exprese MeSH
• testy nádorových kmenových buněk MeSH
• transkriptom MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glukosa MeSH
• glykokonjugáty MeSH
• molekuly buněčné adheze MeSH
• proteiny usnadňující transport glukosy MeSH