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 antitumorózní 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
Triple-negative breast cancers (TNBC) comprise a heterogeneous subgroup of tumors with a generally poor prognosis. Subclassification of TNBC based on genomic analyses shows that basal-like TNBCs, specifically the basal A or BL2 subtype, are characterized by the expression of ΔNp63, a transcription factor that has been attributed a variety of roles in the regulation of proliferation, differentiation, and cell survival. To investigate the role(s) of p63 in basal-like breast cancers, we used HCC1806 cells that are classified as basal A/BL2. We show that these cells endogenously express p63, mainly as the ΔNp63α isoform. TP63 gene knockout by CRISPR resulted in viable cells that proliferate more slowly and adhere less tightly, with an increased rate of migration. Analysis of adhesion-related gene expression revealed a complex set of alterations in p63-depleted cells, with both increased and decreased adhesion molecules and adhesion substrates compared to parental cells expressing p63. Examination of the phenotype of these cells indicated that endogenous p63 is required to suppress the expression of luminal markers and maintain the basal epithelial phenotype, with increased levels of both CK8 and CK18 and a reduction in N-cadherin levels in cells lacking p63. On the other hand, the level of CK5 was not decreased and ER was not increased, indicating that p63 loss is insufficient to induce full luminal-type differentiation. Taken together, these data demonstrate that p63 exerts multiple pro-oncogenic effects on cell differentiation, proliferation and adhesion in basal-like breast cancers.
- MeSH
- buněčná adheze MeSH
- buněčná diferenciace MeSH
- CD antigeny biosyntéza genetika MeSH
- CRISPR-Cas systémy MeSH
- epitelové buňky metabolismus patologie MeSH
- fenotyp MeSH
- genový knockout MeSH
- kadheriny biosyntéza genetika MeSH
- karcinom patologie MeSH
- keratiny biosyntéza genetika MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny fyziologie MeSH
- nádorové supresorové proteiny nedostatek fyziologie MeSH
- proliferace buněk MeSH
- protein - isoformy fyziologie MeSH
- regulace genové exprese u nádorů MeSH
- transkripční faktory nedostatek fyziologie MeSH
- triple-negativní karcinom prsu patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The toxic modes of action of non-dioxin-like polychlorinated biphenyls (PCBs) in liver cells are still only partially understood. Several recent studies have indicated that PCBs may interfere with cell membrane protein functions. Therefore, we analyzed in the present study the effects of di-ortho-substituted 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) on proteins involved in the formation of adherens junctions in a model of rat liver progenitor cells - WB-F344 cell line. PCB 153, at micromolar concentrations, induced a gradual degradation of E-cadherin, beta-catenin or plakoglobin (gamma-catenin) proteins. This effect was not due to changes in gene expression, as PCB 153 had no effect on mRNA levels of the above mentioned proteins. Moreover, apart from the reduction of total beta-catenin pool, PCB 153 also decreased levels of the active beta-catenin form, dephosphorylated at residues Ser37 and Thr41, which is the key co-activator of Wnt-induced TCF/LEF-dependent gene expression. Therefore, we also evaluated the impact of PCB 153 on expression of Axin2, a known transcriptional target of canonical Wnt signaling. PCB 153 reduced basal Axin2 mRNA levels and it inhibited induction of Axin2 expression by recombinant mouse Wnt3a. Nevertheless, PCB 153 had no effect on phosphorylation of glycogen synthase kinase-3beta (GSK-3beta), which is supposed to target beta-catenin for its proteasomal degradation. This suggested that GSK-3beta activity is not modulated by PCB 153 and, consequently, not involved in the observed PCB 153-induced decrease of both total and active beta-catenin levels. Protein levels of E-cadherin and beta-catenin were partially restored with lysosomal inhibitor leupeptin, thus suggesting a possible role of lysosomes in the observed degradation of adherens junction proteins. Taken together, the present data suggest that PCB 153 may interfere with functions of adherens junction proteins involved in both cell-to-cell communication and intracellular signaling. Such mechanisms might be involved in the effects of non-dioxin-like PCBs contributing to liver tumor promotion.
- MeSH
- adhezní spoje metabolismus účinky léků MeSH
- beta-katenin antagonisté a inhibitory biosyntéza genetika MeSH
- buněčné linie MeSH
- epitelové buňky cytologie metabolismus účinky léků MeSH
- fosforylace účinky léků MeSH
- gama-katenin biosyntéza genetika metabolismus MeSH
- genetická transkripce účinky léků MeSH
- inhibitory cysteinových proteinas farmakologie MeSH
- játra cytologie metabolismus účinky léků MeSH
- kadheriny biosyntéza genetika metabolismus MeSH
- kinasa 3 glykogensynthasy metabolismus MeSH
- kmenové buňky cytologie metabolismus účinky léků MeSH
- krysa rodu rattus MeSH
- leupeptiny farmakologie MeSH
- lyzozomy metabolismus MeSH
- messenger RNA biosyntéza genetika MeSH
- polychlorované bifenyly toxicita MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- represorové proteiny biosyntéza genetika metabolismus MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- 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
