Cadherins
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Epigenetic aberrations are well known to play an important role in carcinogenesis, and also have a great potential to serve as biomarkers in many types of cancers, including ovarian cancer in which sensitive and specific biomarkers and detection methods are critically needed. The aim of this study was to investigate methylation of cadherin genes CDH10, CDH13 and CDH18 in ovarian cancer tissue by comparison with control tissue. The study group consisted of 38 patients with ovarian cancer and 25 control patients. For detection of epigenetic events we used next generation sequencing, the most important data were confirmed using high-resolution melting analysis and real-time PCR. We observed significantly higher methylation in CDH13, sporadic methylation in CDH10 and loss of methylation in CDH18 in the ovarian cancer group compared with the control group. These observations suggest that changes in methylation of cadherin genes may be one of the major mechanisms associated with ovarian cancer progression. In addition, because of the high frequency of methylation of the CDH13 gene in the early stages of ovarian cancer, the analyzed CpG sites might be good targets for next study of potential ovarian cancer screening biomarkers.
- MeSH
- dospělí MeSH
- kadheriny genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- metylace DNA * MeSH
- mladý dospělý MeSH
- mucinózní adenokarcinom genetika patologie MeSH
- nádorové biomarkery genetika MeSH
- nádory endometria genetika patologie MeSH
- nádory vaječníků genetika patologie MeSH
- následné studie MeSH
- prognóza MeSH
- promotorové oblasti (genetika) MeSH
- regulace genové exprese u nádorů * MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- serózní cystadenokarcinom genetika patologie MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Adhesion between Sertoli cells and germ cells is important for spermatogenesis. Cadherins are Ca(2+)-dependent transmembrane proteins that mediate cell-cell adhesion. The aim of this study was to compare the expression of P-cadherin in unilaterally cryptorchid and busulphan-treated rat testes using immunohistochemistry. The pattern of expression of P-cadherin in the seminiferous epithelium changed with the stage of the seminiferous epithelium. The membranes of round spermatids and membranes and cytoplasm of spermatocytes were strongly positive. Our experiments revealed that busulphan treatment (2 doses - 10 mg/kg of body weight - 21 days apart) and cryptorchism led to destructive changes in the structure of seminiferous tubules, together with the decrease in P-cadherin expression. The expression of P-cadherin disappeared in the spermatids segregated from the epithelium while segregated spermatocytes remained still positive for P-cadherin during the 3- to 11-day cryptorchid period. In busulphan-treated animals, the expression of P-cadherin was dependent on the presence or absence of the spermatocytes and spermatids in the tubules. Strong positivity for P-cadherin was observed in the spermatocytes that re-appeared in the regenerating seminiferous epithelium. We suggest that P-cadherin participates in the architecture of adherens junctions in testis, plays an important role in maintaining normal spermatogenesis and that cryptorchism and busulphan treatment lead to adherens junction disintegration.
- MeSH
- busulfan farmakologie MeSH
- financování organizované MeSH
- imunohistochemie MeSH
- kadheriny metabolismus MeSH
- kryptorchismus metabolismus MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- testis metabolismus účinky léků MeSH
- velikost orgánu MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
BACKGROUND: Anaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory. METHODS: We investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models. RESULTS: Recurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the β-catenin and YAP1 pathways, which play crucial roles in tumor growth, and conferred resistance to chemotherapy. Furthermore, STAT1 and STAT3 were hyper-activated in these cells. Gene expression profiling showed global changes in pathways related to cell adhesion, cytoskeletal organization, and oncogenic signaling. Notably, FAT mutations associated with poor outcome in patients. CONCLUSIONS: These findings provide novel insights into the molecular portrait of ALCL, that could help improve treatment strategies and the prognosis for ALCL patients.
- MeSH
- anaplastický velkobuněčný lymfom * genetika patologie farmakoterapie MeSH
- fenotyp MeSH
- kadheriny * genetika MeSH
- lidé MeSH
- mutace * MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- prognóza MeSH
- sekvenování exomu MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Trichofolliculomas and trichoepitheliomas are benign skin neoplasms originating from hair follicle cells. They result from defects in the signaling pathways that regulate hair follicle morphogenesis and regeneration. Thus they seem to be an excellent model of these processes. It is known that the E-cadherin/beta-catenin system of adhesion molecules plays a crucial role in the maintenance of tissue architecture. AIM: The aim of the present study was to investigate their involvement in benign hair follicle tumor development. METHODS: Semiquantitative intensity of expression were examined in formalin-fixed and paraffin-embedded tissue sections of 53 trichoepitheliomas, 15 trichofolliculomas and 19 normal skin samples by indirect immunohistochemistry. RESULTS: The intensity of E-cadherin/beta-catenin expression in tumor cells did not differ from controls. However, normal hair follicles cells exhibited membranous E-cadherin/beta-catenin expression, whereas both types of tumors, particularly trichoepitheliomas, showed E-cadherin/beta-catenin expression with a predominantly cytoplasmic localization. CONCLUSIONS: We suggest that this dystopic distribution of the E-cadherin/beta-catenin complex in hair follicle tumor cells may be a marker of cell-cell adhesion disruption which may contribute to the tumor formation.
- MeSH
- bazocelulární nádory chemie MeSH
- beta-katenin analýza MeSH
- imunohistochemie MeSH
- kadheriny analýza MeSH
- lidé MeSH
- nádory kůže chemie MeSH
- nemoci vlasů metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Human embryonic stem cells (hESCs) have unique abilities that enable their use in cell therapy, disease modeling, and drug development. Their derivation is usually performed using a feeder layer, which is undefined and can potentially cause a contamination by xeno components, therefore there is a tendency to replace feeders with xeno-free defined substrates in recent years. Three hESC lines were successfully derived on the vitronectin with a truncated N-terminus (VTN-N) in combination with E-cadherin in xeno-free conditions for the first time, and their undifferentiated state, hESC morphology, and standard karyotypes together with their potential to differentiate into three germ layers were confirmed. These results support the conclusion that the VTN-N/E-cadherin is a suitable substrate for the xeno-free derivation of hESCs and can be used for the derivation of hESCs according to good manufacturing practices.
- MeSH
- buněčná a tkáňová terapie MeSH
- kadheriny genetika MeSH
- lidé MeSH
- lidské embryonální kmenové buňky * MeSH
- obchod MeSH
- vitronektin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
E-cadherin je transmembranózní kalcium-dependentní protein zodpovědný za mezibuněčnou adhezi epiteliálnich buněk, spolu s intracytoplazmatickými proteiny zvanými cateniny vytvárí cadherin-cateninový komplex, který zaručuje integritu tkání. Cílem studie bylo porovnat expresi E-cadherinu s pětiletým přežitím u nemocných po chirurgické resekci pro časná stadia nemalobuněčné plicní rakoviny. V retrospektivní studii jsme porovnali 51eté přežití u 105 nemocných po resekci pro nemalobuněčnou plicní rakovinu ve stadiu I TNM klasifikace s expresí jmenovaného proteinu. K jejich průkazu jsme použili neprímou imunoperoxidázovou reakci na archivních parafínových bločcích. Pozitivita E-cadherinu byla prokázána v 83 prípadech (79 %) resekovaných píleních karcinomů stadia I TNM klasifikace (73 %). 5leté přežití ve sledované skupině nemocných bylo 63 % s mediánem 77 měsíců. Ztráta exprese E-cadherinu korelovala u nádorů jak se zkráceným přežitím, tak s kratší dobou do progrese na hladině pravděpodobnosti p < 0,01. Závěr: Snížená exprese E-cadherinu je vázána na zkrácené přežití po resekci pro nemalobuněčný plicní karcinom ve stadiu I TNM klasifikace.
E-cadherine is a transmembranous calcium-dependent protein responsible for intercellular adhesion of epithefial cells; with the intracytoplasmic proteins called catenins it forms the cadherine-catenin complex that ensures tissue integrity. The purpose of the study was to compare E-cadherine expression with a five-year survival in patients after surgical lung resection because of early-stage non-small-cell lung cancer. In a retrospective study we compared a 5-year survival in 105 patients, who underwent a lung resection because of non-small-cell lung cancer in stage I according to TNM classification, with the expression of the investigated protein. Its presence was established by an indirect immunoperoxidase reaction on archival paraffin blocs. E-cadherin positivity was established in 83 cases (79 %) of resected lung carcinomas in stage I according to TNM classifiction (73 %). A 5-year survival in the investigated group of patients was 63%, with a mean survival of 77 months. In tumours a loss of E-cadherine expression correlated with both shorter survival and a shorter period towards progression at a probability level of p < 0.01. Conclusions: A weaker expression of E-cadherine goes hand in hand with shorter survival after lung resection undertaken in cases of non-small-cell lung carcinoma in stage I of TNM classification.
- MeSH
- finanční podpora výzkumu jako téma MeSH
- kadheriny biosyntéza krev MeSH
- lidé MeSH
- nádory plic chirurgie mortalita MeSH
- nemalobuněčný karcinom plic chirurgie klasifikace mortalita MeSH
- přežití MeSH
- prognóza MeSH
- staging nádorů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
Iron overload causes tissue damage in the liver, but its initial effects at the molecular and cellular level are not well understood. Epithelial cadherin (E-cad) is a major adhesion protein in adherens junctions and is associated with several signal transduction pathways. Dysfunction of E-cad causes instability of adherens junctions, which leads to cell invasion, cell migration, and carcinogenesis. We found in liver samples from iron-overloaded mice that the apparent molecular mass of E-cad was reduced from 125 to 115 kDa in sodium dodecyl sulphate polyacrylamide gel electrophoresis under reducing conditions and immunoblotting, and that the cellular expression of E-cad was decreased in immunohistochemistry. The mRNA level of E-cad, however, did not change significantly, suggesting that the alterations are posttranslational. Interestingly, incubation of control liver extracts with Fe2+ alone also produced the same mobility shift. Neither an oxidant nor an antioxidant influenced this shift in vitro, suggesting that reactive oxygen species, which are generated by iron and known to cause damage to macromolecules, are not involved. Treatment of the 115 kDa E-cad with deferoxamine, an iron chelator, thus removing Fe2+, shifted the molecular mass back to 125 kDa, demonstrating that the shift is reversible. The observation also implies that the alteration that causes the mobility shift is not due to transcriptional control, deglycosylation, and proteolysis. This reversible mobility shift of E-cad has not been previously known. The alteration of E-cad that causes the mobility shift might be an initial step to liver diseases by iron overload.
- MeSH
- játra chemie patofyziologie MeSH
- kadheriny chemie MeSH
- myši MeSH
- posttranslační úpravy proteinů MeSH
- přetížení železem patofyziologie MeSH
- retardační test MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
E-cadherin (E-CD) je pro epitel specifická adhezní molekula, jejíž exprese se, na rozdíl od invaziv- ních duktálních karcinomů, snižuje nebo zcela ztrácí u invazivních lobulárních karcinomů. O tyro- zin kináze c-erbB-2/HER-2/neu je známo, že může expresi adhezního systému, jehož součástí je E- CD, narušit. Vyšetřili jsme 106 případů málo diferencovaných (G2-G3) invazivních karcinomů prsu, z toho 91 IDC, 12 ILC a 3 pleomorfní lobulární karcinomy (PLC). Provedli jsme imunohistochemic- ké barvení estrogenového a progesteronového receptoru (ER/PR), Ki-67, E-CD a c-erbB-2/HER- 2/neu a vyšetřili amplifikaci genu pro c-erbB-2/HER-2/neu pomocí fluorescenční in situ hybridiza- ce. Amplifikace genu pro c-erbB-2/HER-2/neu byla pozorována u 55/91 (60,4 %) IDC, 3/12 (25 %) ILC a 1/3 (33,3 %) PLC a byla asociována s pozitivitou axilárních lymfatických uzlin. Ke ztrátě exprese E-CD došlo u 14/91 (15,4%) IDC, 10/12 (83,3 %) ILC a 2/3 (66,7 %) PLC. Ztráta imunoreaktivity E-CD v IDC byla asociována s amplifikací genu pro c-erbB-2/HER-2/neu, negativitou ER/PR a pozitivní- mi lymfatickými uzlinami, zatímco ILC s pozitivním E-CD byly obvykle HER-2/neu pozitivní. Exprese E-CD má pravděpodobné odlišný biologický význam v málo diferencovaných IDC a ILC. Signální dráha c-erbB-2/HER-2/neu může ovlivnit expresi E-CD ve většině invazivních duktálních karcinomech prsu in vivo.
E-cadherin (E-CD) is an epithelial-specific cell adhesion molecule, whose expression is lost in invasive lobular (ILC) but not in invasive ductal carcinoma (IDC) of the breast. This cell adhesion system can be disrupted by tyrosine kinase c-erbB-2/HER-2/neu. We examined 106 cases of high- grade invasive breast cancer, including 91 IDCs, 12 ILCs and 3 pleomorphic lobular carcinomas (PLCs). We determined Nottingham histological grade and performed immunohistochemistry for estrogen and progesterone receptors (ER/PR), Ki-67, E-CD and c-erbB-2/HER-2/neu with subsequent fluorescence in situ hybridization. Amplification of c-erbB-2/HER-2/neu gene was observed in 55/91 (60.4%) of IDCs, 3/12 (25%) of ILCs and 1/3 (33.3%) of PLCs, and associated with positive axillary lymph nodes. E-CD expression was lost in 14/91 (15.4%) of IDCs, 10/12 (83.3%) of ILCs and 2/3 (66.7%) of PLCs. The loss of E-CD immunoreactivity in IDCs appeared to be associated with c-erbB-2/HER-2/neu gene amplification, negative ER/PR status and positive lymph nodes, whereas E-CD-positive ILCs tended to be HER-2/neu-positive. The biological significance of E-CD expression seems to be different in high-grade IDC and ILC. Oncogenic pathway mediated by c- erbB-2/HER-2/neu may affect the E-CD expression in most invasive ductal breast carcinomas in vivo.
