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  • Last decade has provided a number of studies indicating

    2023-11-24

    Last decade has provided a number of studies indicating that DNA Damage DNA Repair Library mg AhR signaling could play a role both in the development and in progression of multiple cancer types, with potential implications for cancer therapy (for review see (Kolluri et al., 2017; Murray et al., 2014)). Activation of AhR is considered to be the primary mechanism of TCDD and TCDD-like compounds toxicity, which is extensively used in their risk assessment (Larsson et al., 2015; Van den Berg et al., 2006). Nevertheless, it is necessary to identify additional tissue-specific and cell type-specific cellular targets (genes, pathways or TFs), altered upon exposure of cells to toxic AhR ligands. Our results presented here enabled us to compile list of genes, which common expression fingerprint could help to monitor both acute and late changes in AhR signaling in human lung cell model. Since expression of classic AhR gene targets (CYP1A1, CYP1B1, AHRR, TIPARP, ALDH1A3) has been confirmed in a number of different in vitro and in vivo models to be characteristic for TCDD-mediated toxicity, we consider them as “adaptive genes” as their induction is part of the primary response during cellular DNA Damage DNA Repair Library mg to dioxin stress and to deregulated AhR signaling (Das et al., 2017; Jacobs et al., 2011; Kopf et al., 2010; Takemoto et al., 2004; Uno et al., 2004; Prokopec et al., 2017). However, in addition to these well-known AhR targets, we identified several novel gene candidates, which were either induced (GREM1, HIPK2) or repressed (ID1, SOX9) upon short-term TCDD treatment. Notably, although MatInspector tool predicted presence of AhR binding sites only in regulatory regions of HIPK2 and ID1 genes, AhR ChIP-seq experiments confirmed binding of TCDD-activated AhR to regulatory regions of all 4 proposed novel targets (prediction data not shown; Genomatix Software)(GEO acc. no. for ChIP-seq data – GSE90550)(Yang et al., 2017). Interestingly, the identified novel gene candidates have been previously shown to play important roles in lung cancer development. Antagonist of bone morphogenesis proteins 2 and 4 (BMP2, BMP4), gremlin-1 (GREM1) (Church et al., 2015), has been proposed as a potential biomarker for early diagnosis of non-small cell lung cancer, and its overexpression in lung adenocarcinoma cells and in idiopathic pulmonary fibrosis has been documented as well (Koli et al., 2006; Lazar et al., 2013; Mulvihill et al., 2012). HIPK2, previously identified as protein interacting partner of p53, and modulator of its transcriptional activity during e.g. transduction of apoptotic signals (D'Orazi et al., 2002; Hofmann et al., 2002), has recently been reported to be an internal part of Nrf2-Nqo1 signaling axis, which helps lung cancer cells to survive after chemotherapeutic intervention (Torrente et al., 2017). Both NFE2L2/NRF2 and NQO1 themselves have been also already confirmed as direct AhR gene targets (Miao et al., 2005; Tijet et al., 2006). Just recently, expression of sox9b zebrafish gene has been reported to be reduced after TCDD exposure via long non-coding RNA mechanism (Garcia et al., 2017). A unique spatio-temporal expression of SOX9 gene during lung morphogenesis (Danopoulos et al., 2018; Rockich et al., 2013) suggests, that it is of particular interest to monitor expression pattern of this transcription factor in lung tissue, upon exposure to AhR toxic ligands. Importantly, our study suggests that TCDD-like expression pattern of listed genes is generally common also to other classes of AhR ligands, such as PAHs or endogenous AhR ligands. With exception of persistent TCDD, all compounds, at the concentrations used in the present study, were effectively metabolized during first 24 h (endogenous ligands; data not shown) or within 72 h (BaP, BkF). This resulted in a gradual restoration of AhR protein levels and return to basal status of AhR signaling (Denison and Faber, 2017). Therefore, expression fingerprint of identified set of genes seems to be a part of common AhR-dependent response to diverse classes of AhR ligands in the lung carcinoma model.