Constitutive expression of Ascl1 in the lung delays tobacco-related tumorigenesis via MGMT.

<p>A) MMP-7 mRNA was increased in the lungs of transgenic mice (qRT-PCR). At the 24 week time point, MMP-7 mRNA was detected in only 2 out of 8 WT/Sal mice and 6 out of 8 mice in WT/NNK. B) MGMT mRNA was significantly increased in the lungs of transgenic mice, but revealed no change following the exposure of these mice to NNK (qRT-PCR, n = 6∼11). C) The relative number (%) of MGMT positive cells (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052832#pone.0052832.s001" target="_blank">Fig. S1C</a>) at terminal bronchioles and BOA lesions was increased at 24 weeks in transgenic mice regardless of NNK exposure. D) At 24 weeks the incidence of lung tumors in NNK-exposed transgenic mice was lower than that of WT mice (20% <i>vs</i> 63%; p<0.05). E) At 24 weeks the number of tumors per mouse (multiplicity) was lower in TG/NNK mice than that in WT/NNK mice. F) The size (diameter in millimiters) of surface tumors in both genotypes was comparable and somewhat larger in NNK-exposed mice. G) At 52 weeks both spontaneous and NNK-induced lung tumors in TG mice were alveolar adenomas. E) F) G) Photomicrographs of lung and tumors in transgenic mice at 52 weeks. Both spontaneous and NNK-induced tumors (Tu) were adenomas that grew independent of BOA lesions characteristic of transgenic mouse lungs (H&E staining, green bar = 100 µm). H) Photomicrographs of spontaneous and NNK-induced tumors in transgenic mice at 52 weeks. CC10 was expressed in airway epithelium (Lu) and BOA lesions, while tumors were negative. Pro-SPC was positive in normal alveolar type II cells and tumors, but negative in the epithelium lining airway lumens (Lu). (Immunoperoxidase staining, green bar = 100 µm). (Sal = saline; TG = transgenic; TB = terminal bronchiole; BOA = bronchiolization of alveoli; mean±S.E.M. * P<0.05, ** p<0.01, *** p<0.001).