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. 2024 Jun 18;300(7):107486. doi: 10.1016/j.jbc.2024.107486

Figure 2.

Figure 2

The TCDD-AHR axis activates EGFR signaling. The TCDD-AHR axis upregulated genes were subjected to ingenuity pathway analyses to identify (A) top upstream regulators and (B) top causal networks, with relative p-value (bars) and number of participating molecules (orange line). The EGFR signaling relevant upstream regulators and causal networks are labeled as red bars. C, selective gene expression was measured by qRT-PCR using RNA isolated from HaCaT cells treated with vehicle (DMSO, Ctl), TCDD (T, 10 nM), CH223191 (CH, 10 μM), and TCDD plus CH223191 (T+CH). Relative expression was calculated using the housekeeping gene GAPDH as an internal control and compared to that in Ctl set as 1. D, Western blot analyses of the EGFR pathway activity using antibodies for phosphor (p) and total EGFR and ERK, and β-actin as a loading control. Quantification of (E) p-EGFR/EGFR and (F) p-ERK/ERK ratio of the immunoblotting data, with ratio in Ctl set as 1. The TCDD-exposed Map3k1+/−Egfr+/F (N = 13) and Map3k1+/−Egfr+/ΔOSE (N = 14) fetuses were collected at E17.5 and their eyes were (G) photographed and representative images were shown. The scale bar represents 500 μm, and (H) the areas of open eye were measured. Results were shown as mean ± SEM of at least three independent experiments (N ≥ 3). ∗p < 0.05, ∗∗p < 0.01 and ∗∗∗p < 0.001 were considered statistically significant compared to Ctl (in C, E, and F) and TCDD-treated Map3k1+/−Egfr+/F group (in H). AHR, aryl hydrocarbon receptor; DMSO, dimethyl sulfoxide; EGFR, epidermal growth factor receptor; ERK, extracellular signal regulated kinase; MAP3K1, mitogen-activated protein kinase kinase kinase 1; OSE, ocular surface epithelium; qRT-PCR, quantitative reverse transcription PCR; TCDD, 2,3,7,8-tetrachlorodibenzo-para-dioxin.