Genes expression in xenografts obtained from 15 months cigarette smoke condensate (CSC)-exposed HBEC cells following expression of KRASV12. Homo sapiens

We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells (HBEC) for transformation by a single oncogene. The smoke-induced, chromatin changes include initial repressive polycomb marking of genes later manifesting abnormal DNA methylation by 10 months. At this time, cells manifest epithelial to mesenchymal changes, anchorage-independent growth and upregulated RAS/MAPK signaling with silencing of hyper-methylated genes normally inhibiting these pathways and which are associated with smoking related NSCLC. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adeno-squamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation. Overall design: Gene expression in xenografts obtained from two biological replicates (rep 1 and rep2) of 15 months cigarette smoke condensate (CSC)-exposed HBEC cells following expression of KRASV12. Gene expression in Control cells at the same time point and expressing KRASV12 was used for comparison in final analysis.