Molecules and Cells

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Fig. 4.

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Fig. 4. Sequential molecular events associated with the development of lung AD and progression to ADC. (A) Mice (FVB strain) were intraperitoneally injected with urethane at a dose of 500 mg/kg body weight. Growth of cancer in mouse lungs vs. time after urethane injection is shown. Five mice were used for each time point. Ave, average diameter (mm) of cancer; SD, standard deviation. (B) Mouse lung ADs that developed 20 weeks (20W) after urethane injection and lung ADCs that developed 58 weeks (58W) after injection were analyzed by immunohistochemical (IHC) staining with anti-phospho-Erk (p-Erk) and anti-Runx3 antibodies. Runx3 expression was markedly downregulated in both ADs and ADCs relative to adjacent normal regions. By contrast, Erk was activated only in ADCs. Nor, normal. (C) WT mouse lung and mouse lung ADs developed at 20 weeks (20W, diameter < 1 mm), relatively small lung ADCs (58W-S, diameter ≒ 2 mm) and relatively large lung ADCs (58W-L, diameter ≒ 3 mm) developed at 58 weeks, and large lung ADCs (68W-L, diameter ≒ 6 mm) developed at 68 weeks after urethane injection were obtained. Four ADs or ADCs from each group were analyzed by whole-exon sequencing. Among the known major oncogenes and tumor suppressors involved in lung cancer, only K-Ras mutations were detected. Amino acid changes in K-Ras and the ratio of mutation signal to total signal are shown. d, diameter; ratio, ratio of oncogenic K-Ras–mutated allele relative to total K-Ras. Bar diagram demonstrating average ratios of K-Ras mutation in each group of ADs/ADCs. P = P value. (D) Schematic representation of the molecular events associated with the development of lung ADs and progression into ADCs. Runx3↓ and K-Ras↑ indicate Runx3 inactivation and K-Ras activation, respectively. Human AAH and BAC correspond to mouse lung ADs.
Mol. Cells 2020;43:889~897 https://doi.org/10.14348/molcells.2020.0182
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