Modulation of AhR expression/activity in normal human bronchial epithelial cells during the benzo[a]pyrene-induced epithelial-to-mesenchymal transition

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F24%3AN0000178" target="_blank" >RIV/00027162:_____/24:N0000178 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Modulation of AhR expression/activity in normal human bronchial epithelial cells during the benzo[a]pyrene-induced epithelial-to-mesenchymal transition

Popis výsledku v původním jazyce

The aryl hydrocarbon receptor (AhR) regulates cancer progression in several cancer types. In this study, a chronic (12-week) exposure to benzo[a]pyrene (BaP), which is both AhR-activating and genotoxic environmental contaminant, has been found to induce epithelial-to-mesenchymal transition (EMT) in normal human bronchial epithelial HBEC-12KT cells. Early, after 2-week exposure to BaP, morphological changes were observed that were possibly linked to CDKN1A/p21 and SERPINB2 induction. The upregulation of expression of mesenchymal markers and EMT-related transcription factors, as well as an increased cell migration, were first observed after 8-week exposure to BaP. Both groups of genes were strongly upregulated in transformed mesenchymal-like cells at the end of the treatment. Although exposure to non-genotoxic AhR ligand TCDD itself did not transform HBEC-12KT cells into mesenchymal-like cells, the AhR-regulated gene expression contributed to a stepwise BaP-induced EMT progression. The expression of AhR target genes (CYP1A1, CYP1B1, TIPARP, IL1B, SERPINE1 and SERPINB2) was significantly induced up to 8 weeks of BaP or TCDD exposure; however, it decreased in transformed mesenchymal-like cells. Unlike TCDD, BaP induced CDKN1A/p21 expression, which might be linked to a unique pattern of expression of Krüppel-like factor 6 (KLF6) that has been previously shown to act as a dimerization partner of the AhR. Here, BaP upregulated, while TCDD downregulated KLF6 expression, which might contribute to differential CDKN1A/p21 regulation by BaP. We also identified a significant induction of KYNU (kynureninase) in transformed mesenchymal-like cells, which might contribute to observed downregulation of AhR activity in fully transformed mesenchymal-like cells, via decreasing levels of endogenous AhR agonists. However, the exact mechanism(s) of downregulation of AhR signaling in transformed HBEC-12KT should be further investigated. In conclusion, CDKN1A/p21, pro-inflammatory responses and extracellular matrix remodeling genes were found to be upregulated during BaP-induced bronchial epithelial cell transformation. Their induction probably depends both on the AhR transcriptional activity and on the AhR-dependent metabolism of BaP that yields further active compounds.

Název v anglickém jazyce

Modulation of AhR expression/activity in normal human bronchial epithelial cells during the benzo[a]pyrene-induced epithelial-to-mesenchymal transition

Popis výsledku anglicky

The aryl hydrocarbon receptor (AhR) regulates cancer progression in several cancer types. In this study, a chronic (12-week) exposure to benzo[a]pyrene (BaP), which is both AhR-activating and genotoxic environmental contaminant, has been found to induce epithelial-to-mesenchymal transition (EMT) in normal human bronchial epithelial HBEC-12KT cells. Early, after 2-week exposure to BaP, morphological changes were observed that were possibly linked to CDKN1A/p21 and SERPINB2 induction. The upregulation of expression of mesenchymal markers and EMT-related transcription factors, as well as an increased cell migration, were first observed after 8-week exposure to BaP. Both groups of genes were strongly upregulated in transformed mesenchymal-like cells at the end of the treatment. Although exposure to non-genotoxic AhR ligand TCDD itself did not transform HBEC-12KT cells into mesenchymal-like cells, the AhR-regulated gene expression contributed to a stepwise BaP-induced EMT progression. The expression of AhR target genes (CYP1A1, CYP1B1, TIPARP, IL1B, SERPINE1 and SERPINB2) was significantly induced up to 8 weeks of BaP or TCDD exposure; however, it decreased in transformed mesenchymal-like cells. Unlike TCDD, BaP induced CDKN1A/p21 expression, which might be linked to a unique pattern of expression of Krüppel-like factor 6 (KLF6) that has been previously shown to act as a dimerization partner of the AhR. Here, BaP upregulated, while TCDD downregulated KLF6 expression, which might contribute to differential CDKN1A/p21 regulation by BaP. We also identified a significant induction of KYNU (kynureninase) in transformed mesenchymal-like cells, which might contribute to observed downregulation of AhR activity in fully transformed mesenchymal-like cells, via decreasing levels of endogenous AhR agonists. However, the exact mechanism(s) of downregulation of AhR signaling in transformed HBEC-12KT should be further investigated. In conclusion, CDKN1A/p21, pro-inflammatory responses and extracellular matrix remodeling genes were found to be upregulated during BaP-induced bronchial epithelial cell transformation. Their induction probably depends both on the AhR transcriptional activity and on the AhR-dependent metabolism of BaP that yields further active compounds.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30108 - Toxicology

Projekt

<a href="/cs/project/GA24-10086S" target="_blank" >GA24-10086S: Dopady působení polycyklických aromatických uhlovodíků na buněčné procesy spojené se stresovou signalizací a deregulací metabolismu</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů