Aberrant signaling through β-catenin is an important determinant of tumorigenesis in rodents as well as in humans. In mice, xenobiotic activators of the constitutive androstane receptor (CAR), a chemo-sensing nuclear receptor, promote liver tumor growth by means of a non-genotoxic mechanism and, under certain conditions, select for hepatocellular tumors which contain activated β-catenin. In normal hepatocytes, interactions of β-catenin and CAR have been demonstrated with respect to the induction of proliferation and drug metabolism-related gene expression. The molecular details of these interactions are still not well understood. Recently it has been hypothesized that CAR might activate β-catenin signaling, thus providing a possible explanation for some of the observed phenomena. Nonetheless, many aspects of the molecular interplay of the two regulators have still not been elucidated. This review briefly summarizes our current knowledge about the interplay of CAR and β-catenin. By taking into account data and observations obtained with different mouse models and employing different experimental approaches, it is shown that published data also contain substantial evidence that xenobiotic activators of CAR do not activate, or do even inhibit signaling through the β-catenin pathway. The review highlights new aspects of possible ways of interaction between the two signaling cascades and will help to stimulate scientific discussion about the crosstalk of β-catenin signaling and the nuclear receptor CAR.
- MeSH
- beta-katenin metabolismus MeSH
- hodnocení rizik MeSH
- játra účinky léků metabolismus patologie MeSH
- lidé MeSH
- nádorová transformace buněk chemicky indukované metabolismus patologie MeSH
- nádory jater chemicky indukované metabolismus patologie MeSH
- receptory cytoplazmatické a nukleární agonisté metabolismus MeSH
- rizikové faktory MeSH
- signální dráha Wnt * MeSH
- xenobiotika toxicita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Tamoxifen treatment in breast cancer patients is associated with increased risk of endometrial malignancies. Significantly, higher AGR2 expression was found in endometrial cancers that developed in women previously treated with tamoxifen compared to those who had not been exposed to tamoxifen. An association of elevated AGR2 level with myometrial invasion occurrence and invasion depth was also found. In vitro analyses identified a stimulatory effect of AGR2 on cellular proliferation. Although adverse tamoxifen effects on endometrial cells remain elusive, our work identifies elevated AGR2 as a candidate tamoxifen-dependent mechanism of action responsible for increased incidence of endometrial cancer.
- MeSH
- adenokarcinom chemicky indukované genetika metabolismus patologie MeSH
- antitumorózní látky hormonální toxicita MeSH
- buňky A549 MeSH
- endometrium účinky léků metabolismus patologie MeSH
- invazivní růst nádoru MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorová transformace buněk chemicky indukované genetika metabolismus patologie MeSH
- nádory endometria chemicky indukované genetika metabolismus patologie MeSH
- pohyb buněk účinky léků MeSH
- proliferace buněk účinky léků MeSH
- proteiny genetika metabolismus MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- RNA interference MeSH
- signální transdukce účinky léků MeSH
- tamoxifen toxicita MeSH
- transfekce MeSH
- upregulace MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Since ochratoxin A (OTA) was discovered, it has been ubiquitous as a natural contaminant of moldy food and feed. The multiple toxic effects of OTA are a real threat for human beings and animal health. For example, OTA can cause porcine nephropathy but can also damage poultries. Humans exposed to OTA can develop (notably by inhalation in the development of acute renal failure within 24 h) a range of chronic disorders such as upper urothelial carcinoma. OTA plays the main role in the pathogenesis of some renal diseases including Balkan endemic nephropathy, kidney tumors occurring in certain endemic regions of the Balkan Peninsula, and chronic interstitial nephropathy occurring in Northern African countries and likely in other parts of the world. OTA leads to DNA adduct formation, which is known for its genotoxicity and carcinogenicity. The present article discusses how renal carcinogenicity and nephrotoxicity cause both oxidative stress and direct genotoxicity. Careful analyses of the data show that OTA carcinogenic effects are due to combined direct and indirect mechanisms (e.g., genotoxicity, oxidative stress, epigenetic factors). Altogether this provides strong evidence that OTA carcinogenicity can also occur in humans.
- MeSH
- balkánská nefropatie chemicky indukované genetika dějiny metabolismus MeSH
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- epigeneze genetická účinky léků MeSH
- hodnocení rizik MeSH
- ledviny účinky léků metabolismus patologie MeSH
- lidé MeSH
- nádorová transformace buněk chemicky indukované genetika metabolismus MeSH
- nádory ledvin chemicky indukované genetika dějiny metabolismus MeSH
- ochratoxiny dějiny metabolismus toxicita MeSH
- oxidační stres účinky léků MeSH
- poškození DNA MeSH
- potravinářská mikrobiologie * dějiny trendy MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- rizikové faktory MeSH
- toxikologie * dějiny trendy MeSH
- zvířata MeSH
- Check Tag
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- historické články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Polycyclic aromatic hydrocarbons (PAHs) with lower molecular weight exhibit lesser genotoxicity and carcinogenicity than highly carcinogenic PAHs with a higher number of benzene rings. Nevertheless, they elicit specific effects linked with tumor promotion, such as acute inhibition of gap junctional intercellular communication (GJIC). Although inflammatory reaction may alter bioactivation and toxicity of carcinogenic PAHs, little is known about the impact of pro-inflammatory cytokines on toxic effects of the low-molecular-weight PAHs. Here, we investigated the impact of a pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), on the effects associated with tumor promotion and with induction of the aryl hydrocarbon receptor (AhR)-dependent gene expression in rat liver epithelial cells. We found that a prolonged incubation with TNF-α induced a down-regulation of GJIC, associated with reduced expression of connexin 43 (Cx43), a major connexin isoform found in liver epithelial cells. The Cx43 down-regulation was partly mediated by the activity of the mitogen-activated protein (MAP) p38 kinase. Independently of GJIC modulation, or p38 activation, TNF-α potentiated the AhR-dependent proliferative effect of a model low-molecular-weight PAH, fluoranthene, on contact-inhibited cells. In contrast, this pro-inflammatory cytokine repressed the fluoranthene-induced expression of a majority of model AhR gene targets, such as Cyp1a1, Ahrr or Tiparp. The results of the present study indicate that inflammatory reaction may differentially modulate various toxic effects of low-molecular-weight PAHs; the exposure to pro-inflammatory cytokines may both strengthen (inhibition of GJIC, disruption of contact inhibition) and repress (expression of a majority of AhR-dependent genes) their impact on toxic endpoints associated with carcinogenesis.
- MeSH
- aktivace enzymů MeSH
- buněčné linie MeSH
- časové faktory MeSH
- epitelové buňky účinky léků metabolismus patologie MeSH
- fluoreny toxicita MeSH
- genetická transkripce účinky léků MeSH
- játra účinky léků metabolismus patologie MeSH
- konexin 43 genetika metabolismus MeSH
- krysa rodu rattus MeSH
- mezerový spoj účinky léků metabolismus patologie MeSH
- mezibuněčná komunikace účinky léků MeSH
- mitogenem aktivované proteinkinasy p38 metabolismus MeSH
- molekulová hmotnost MeSH
- nádorová transformace buněk chemicky indukované metabolismus patologie MeSH
- nádory jater chemicky indukované metabolismus patologie MeSH
- proliferace buněk účinky léků MeSH
- receptory aromatických uhlovodíků agonisté genetika metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- signální transdukce účinky léků MeSH
- TNF-alfa toxicita MeSH
- transkripční faktory bHLH agonisté genetika metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zánět chemicky indukované genetika metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The aryl hydrocarbon receptor (AhR) contributes to the control of cell-to-cell communication, cell adhesion, migration or proliferation. In the present study, we investigated the regulation of connexin43 (Cx43) and Cx43-mediated gap junctional intercellular communication (GJIC) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells. The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells, which is frequently abolished in cancer cells; however, the mechanisms contributing to its disruption are still only partially understood. Disruption of contact inhibition, which was induced by toxic AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells, reduced Cx43 protein levels, possibly via enhanced proteasomal degradation, significantly decreased the amount of gap junction plaques and downregulated GJIC, in an AhR-dependent manner. Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD, siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells. Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition, which occurs at the post-transcriptional level. This process runs in parallel with alterations of other forms of cell-to-cell communication, thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC, two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression.
- MeSH
- benz(a)anthraceny toxicita MeSH
- buněčné linie MeSH
- časové faktory MeSH
- down regulace MeSH
- epitelové buňky účinky léků metabolismus patologie MeSH
- floroglucinol analogy a deriváty farmakologie MeSH
- fluoreny toxicita MeSH
- fosforylace MeSH
- genový knockdown MeSH
- indoly farmakologie MeSH
- játra účinky léků metabolismus patologie MeSH
- karcinogeny toxicita MeSH
- konexin 43 genetika metabolismus MeSH
- kontaktní inhibice účinky léků MeSH
- krysa rodu rattus MeSH
- ligandy MeSH
- mezerový spoj účinky léků metabolismus patologie MeSH
- mezibuněčná komunikace účinky léků MeSH
- nádorová transformace buněk chemicky indukované metabolismus patologie MeSH
- nádory jater chemicky indukované metabolismus patologie MeSH
- polychlorované dibenzodioxiny toxicita MeSH
- proliferace buněk MeSH
- proteasomový endopeptidasový komplex metabolismus MeSH
- receptory aromatických uhlovodíků agonisté genetika metabolismus MeSH
- RNA interference MeSH
- signální transdukce účinky léků MeSH
- transfekce MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- Alphapapillomavirus MeSH
- Bacteroides MeSH
- bakteriální infekce komplikace metabolismus mikrobiologie patofyziologie MeSH
- bakteriální toxiny škodlivé účinky MeSH
- cyklooxygenasa 2 metabolismus MeSH
- Cytomegalovirus MeSH
- Escherichia coli MeSH
- Helicobacter pylori MeSH
- kolorektální nádory mikrobiologie patofyziologie virologie MeSH
- lidé MeSH
- nádorová transformace buněk chemicky indukované metabolismus MeSH
- NF-kappa B metabolismus MeSH
- patologická angiogeneze metabolismus patofyziologie MeSH
- poškození DNA MeSH
- Streptococcus bovis MeSH
- virové nemoci komplikace metabolismus patofyziologie virologie MeSH
- virus Epsteinův-Barrové MeSH
- virus JC MeSH
- volné radikály metabolismus MeSH
- zánět metabolismus patofyziologie MeSH
- Check Tag
- lidé MeSH
Elevated levels of survivin, telomerase catalytic subunit (TERT), integrin-linked kinase (ILK), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS) and the regulatory factors c-MYB and Tcf-4 are often found in human cancers including colorectal cancer (CRC) and have been implicated in the development and progression of tumorigenesis. The aim of this study was to determine the expression of these genes in mouse models of sporadic and colitis-associated CRC. To address these issues, we used qRT-PCR approach to determine changes in gene expression patterns of neoplastic cells (high-grade dysplasia/intramucosal carcinoma) and surrounding normal epithelial cells in A/J and ICR mouse strains using laser microdissection. Both strains were injected with azoxymethane and ICR mice were also given drinking water that contained 2% dextran sodium sulphate. In both sporadic (A/J mice) and colitis-associated (ICR mice) models of CRC, the levels of TERT mRNA, COX-2 mRNA and Tcf-4 mRNA were higher in neoplastic cells than in surrounding normal epithelial cells. In contrast, survivin mRNA was upregulated only in neoplastic cells from A/J mice and ILK mRNA was upregulated only in neoplastic cells from ICR mice. However, the expression of iNOS mRNA was similar in normal and neoplastic cells in both models and c-MYB mRNA was actually downregulated in neoplastic cells compared with normal cells in both models. These findings suggest that the genetic background and/or the molecular mechanisms of tumorigenesis associated with genotoxic insults and colonic inflammation influence the gene expression of mTERT, COX-2, Tcf-4, c-MYB, ILK and survivin in colon epithelial neoplasia.
- MeSH
- apoptóza genetika MeSH
- azoxymethan MeSH
- cyklooxygenasa 2 genetika MeSH
- inhibitory apoptózy MeSH
- kolitida genetika chemicky indukované komplikace patologie MeSH
- mikrodisekce MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední ICR MeSH
- myši MeSH
- nádorová transformace buněk genetika chemicky indukované MeSH
- nádory tračníku genetika chemicky indukované patologie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- progrese nemoci MeSH
- proliferace buněk MeSH
- protein-serin-threoninkinasy genetika MeSH
- proteiny asociované s mikrotubuly genetika MeSH
- proteiny buněčného cyklu genetika MeSH
- proteiny regulující apoptózu genetika MeSH
- protoonkogenní proteiny c-myb genetika MeSH
- regulace genové exprese u nádorů MeSH
- represorové proteiny MeSH
- síran dextranu MeSH
- stanovení celkové genové exprese metody MeSH
- synthasa oxidu dusnatého, typ II genetika MeSH
- telomerasa genetika MeSH
- transkripční faktory BHLH-Zip genetika MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- antioxidancia MeSH
- fyziologie výživy MeSH
- jedlé rostliny chemie MeSH
- lidé MeSH
- nádorová transformace buněk fyziologie chemicky indukované prevence a kontrola MeSH
- nádory prsu etiologie prevence a kontrola MeSH
- nenasycené mastné kyseliny MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- buněčné linie MeSH
- křečci praví MeSH
- mezibuněčná komunikace účinky léků MeSH
- nádorová transformace buněk chemicky indukované účinky léků MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- benzopyreny toxicita MeSH
- embryo savčí cytologie účinky léků MeSH
- křečci praví MeSH
- methansulfonáty toxicita MeSH
- methylcholanthren toxicita MeSH
- nádorová transformace buněk chemicky indukované MeSH
- nitrosoguanidiny toxicita MeSH
- nitrosomočovinové sloučeniny toxicita MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- zvířata MeSH