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. 2023 Apr 16;83(12):1953–1967. doi: 10.1158/0008-5472.CAN-22-3848

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©2023 The Authors; Published by the American Association for Cancer Research

This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.

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Figure 4. Keap1/Nrf2 mutation cooperates with KrasG12D/+ to promote lung tumor initiation and early progression. A, Overall survival of Keap1 mutant mice with KrasG12D/+ mutation. Keap1+/+ (n = 16); Keap1R554Q/+ (n = 18); Keap1R554Q/R554Q (n = 18). B, Overall survival of Nrf2 mutant mice with KrasG12D/+ mutation. Nrf2+/+ (n = 14); Nrf2D29H/+ (n = 12). ns, not significant [log-rank (Mantel–Cox) test]. C, Representative IHC staining of Nrf2 in Keap1/Nrf2 mutant tumors with KrasG12D/+ mutation. Scale bars, 20 μm. D, H-scores for Nrf2 (nuclear) IHC staining. E, Representative IHC staining of Nrf2 target Nqo1. Scale bars, 20 μm. F, H-scores for Nqo1 (whole cell) IHC staining. C–F, N = 3 mice per genotype and >20,000 tumor cells per mouse. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 (one-way ANOVA). G, Representative whole-lung hematoxylin and eosin–stained section. Scale bars, 2,000 μm. H, Tumor number per mouse in Keap1/Nrf2 mutant models normalized to lung area. *, P < 0.05; **, P < 0.01 (one-way ANOVA). I, Distribution of tumor grades across Keap1/Nrf2 mutant models. *, P < 0.05; **, P < 0.01 (unpaired t test with Holm–Sidak multiple comparisons test). AAH, atypical adenomatous hyperplasia; BH, bronchiolar hyperplasia. J, Fraction of lung tumor burden by grade (lung tumor area/total lung area per grade). *, P < 0.05 (unpaired t test with Holm–Sidak multiple comparisons test). I and J, n = 10 mice and ≥2,000 tumors per genotype. — Keap1/Nrf2 mutation cooperates with Kras^G12D/+ to promote lung tumor initiation and early progression. A, Overall survival of Keap1 mutant mice with Kras^G12D/+ mutation. Keap1^+/+ (n = 16); Keap1^R554Q/+ (n = 18); Keap1^R554Q/R554Q (n = 18). B, Overall survival of Nrf2 mutant mice with Kras^G12D/+ mutation. Nrf2^+/+ (n = 14); Nrf2^D29H/+ (n = 12). ns, not significant [log-rank (Mantel–Cox) test]. C, Representative IHC staining of Nrf2 in Keap1/Nrf2 mutant tumors with Kras^G12D/+ mutation. Scale bars, 20 μm. D, H-scores for Nrf2 (nuclear) IHC staining. E, Representative IHC staining of Nrf2 target Nqo1. Scale bars, 20 μm. F, H-scores for Nqo1 (whole cell) IHC staining. C–F,N = 3 mice per genotype and >20,000 tumor cells per mouse. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 (one-way ANOVA). G, Representative whole-lung hematoxylin and eosin–stained section. Scale bars, 2,000 μm. H, Tumor number per mouse in Keap1/Nrf2 mutant models normalized to lung area. *, P < 0.05; **, P < 0.01 (one-way ANOVA). I, Distribution of tumor grades across Keap1/Nrf2 mutant models. *, P < 0.05; **, P < 0.01 (unpaired t test with Holm–Sidak multiple comparisons test). AAH, atypical adenomatous hyperplasia; BH, bronchiolar hyperplasia. J, Fraction of lung tumor burden by grade (lung tumor area/total lung area per grade). *, P < 0.05 (unpaired t test with Holm–Sidak multiple comparisons test). I and J,n = 10 mice and ≥2,000 tumors per genotype.