Sloncová, E*
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Trophoblastic cell surface antigen 2 (TROP2) is a membrane glycoprotein overexpressed in many solid tumors with a poor prognosis, including intestinal neoplasms. In our study, we show that TROP2 is expressed in preneoplastic lesions, and its expression is maintained in most colorectal cancers (CRC). High TROP2 positivity correlated with lymph node metastases and poor tumor differentiation and was a negative prognostic factor. To investigate the role of TROP2 in intestinal tumors, we analyzed two mouse models with conditional disruption of the adenomatous polyposis coli (Apc) tumor-suppressor gene, human adenocarcinoma samples, patient-derived organoids, and TROP2-deficient tumor cells. We found that Trop2 is produced early after Apc inactivation and its expression is associated with the transcription of genes involved in epithelial-mesenchymal transition, the regulation of migration, invasiveness, and extracellular matrix remodeling. A functionally similar group of genes was also enriched in TROP2-positive cells from human CRC samples. To decipher the driving mechanism of TROP2 expression, we analyzed its promoter. In human cells, this promoter was activated by β-catenin and additionally by the Yes1-associated transcriptional regulator (YAP). The regulation of TROP2 expression by active YAP was verified by YAP knockdown in CRC cells. Our results suggest a possible link between aberrantly activated Wnt/β-catenin signaling, YAP, and TROP2 expression.
- Publikační typ
- časopisecké články MeSH
beta-catenin has a dual function; it is implicated in intercellular junctions and transcriptional co-activation. Here we examined the regulation of the expression and localization of beta-catenin in HT29 colorectal adenocarcinoma cells. Our results showed that inhibition of PI-3 kinase with wortmannin was accompanied by a considerably reduced expression of beta-catenin. This effect was overcome by butyrate and occurred at the protein level, not at the level of mRNA. Moreover, NaBT significantly increased the phosphorylation of the ribosomal protein, S6, known to participate in the translational control of gene expression. This was accompanied by the increased phosphorylation of p70 S6K and MAPKs, the effector proteins that are upstream of protein S6 in the distinct signaling pathways. These facts indicate that different signaling pathways may be involved in the regulation of beta-catenin synthesis. Modulation of beta-catenin expression induced by NaBT appeared to occur at the level of protein translation, suggesting that NaBT may act as a translational regulator.
- MeSH
- adenokarcinom metabolismus MeSH
- alkalická fosfatasa metabolismus MeSH
- androstadieny metabolismus MeSH
- beta-katenin genetika metabolismus MeSH
- butyráty metabolismus MeSH
- financování organizované MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- fosforylace MeSH
- imunohistochemie MeSH
- inhibitory fosfoinositid-3-kinasy MeSH
- kinasy ribozomálního proteinu S6, 70-kDa metabolismus MeSH
- kinasy ribozomálního proteinu S6 metabolismus MeSH
- kolorektální nádory metabolismus MeSH
- lidé MeSH
- mitogenem aktivované proteinkinasy metabolismus MeSH
- nádorové buněčné linie MeSH
- serin metabolismus MeSH
- signální transdukce fyziologie MeSH
- tyrosin metabolismus MeSH
- Check Tag
- lidé MeSH
CART (cocaine- and amphetamine-regulated transcript) peptides have been studied for ten years. We report specific binding of 125I-CART(61-102) to the rat adrenal pheochromocytoma PC12 cell line, both intact cells and cell membranes. Saturation binding to intact plated cells resulted in Kd of 0.48+/-0.16 nM and Bmax of 2228+/-529 binding sites/cell. 125I-CART(61-102) was also bound to PC12 cells differentiated using nerve growth factor to the neuronal phenotype with non-specific binding below 20%, and Kd of 1.90+/-0.27 nM and Bmax of 11,194+/-261 binding sites/cell. In competitive binding experiments, CART(61-102), CART(55-102) and di-iodinated CART(61-102) were bound to PC12 cell membranes with Ki in low nM range; their affinity to intact non-differentiated and differentiated cells was in low 10(-8) M range. In order to prove that iodination did not eliminate the pharmacological properties of CART, we tested the biological activity of di-iodinated CART(61-102). It decreased food intake in in vivo feeding experiment on fasted mice in a dose of 1 microg/mouse to the same extent as CART(61-102) in a dose of 0.5 microg/mouse.
- MeSH
- biologické modely MeSH
- buněčná diferenciace účinky léků MeSH
- buněčná membrána metabolismus MeSH
- buňky PC12 MeSH
- časové faktory MeSH
- fenotyp MeSH
- feochromocytom MeSH
- financování organizované MeSH
- izotopy jodu metabolismus MeSH
- kinetika MeSH
- krysa rodu rattus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádory nadledvin MeSH
- neurony metabolismus patologie MeSH
- neurotrofní faktory farmakologie MeSH
- peptidové fragmenty metabolismus MeSH
- přijímání potravy účinky léků MeSH
- proteiny nervové tkáně farmakologie metabolismus MeSH
- radioizotopy jodu metabolismus MeSH
- vazba proteinů MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- MeSH
- eukaryotický iniciační faktor 2B fyziologie MeSH
- finanční podpora výzkumu jako téma MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- inhibitory fosfoinositid-3-kinasy MeSH
- králíci MeSH
- protoonkogenní proteiny metabolismus MeSH
- viry ptačího sarkomu patogenita MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
