Pathogenic mechanisms of lung adenocarcinoma in smokers and non-smokers determined by gene expression interrogation.

Abstract

Cigarette smoking is the leading risk factor for lung cancer, which accounts for the highest number of cancer-related mortalities worldwide in men and women. Individuals with a history of smoking are 15-30 times more likely to develop lung cancer compared with those who do not smoke. However, our understanding of the underlying molecular mechanisms that contribute to lung tumorigenesis in smokers versus non-smokers remains incomplete. In order to investigate such mechanisms, the present study aimed to systemically interrogate microarray datasets from tumor biopsies and matching normal tissues from stage I and II lung adenocarcinoma patients who had never smoked or were current smokers. The gene expression analysis identified 422 (99 upregulated and 323 downregulated) and 534 (174 upregulated and 360 downregulated) differentially-expressed genes from the never-smokers and current smokers, respectively, and the two groups shared 277 genes that exhibited similar trends of alteration. These genes encode regulators that are involved in a variety of cellular functions, including collagen metabolism and homeostasis of caveolae plasma membranes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes characterization indicated that biological pathways, including extracellular matrix-receptor interaction and cell migration and proliferation, were all affected in the lung cancer patients regardless of the smoking status. However, smoking induced a unique gene expression pattern characterized by upregulation of cell cycle regulators (CDK1, CCNB1 and CDC20), as well as significantly affected biological networks, including p53 signaling pathways. Taken together, these findings suggest novel mechanistic insights, and provide an improved understanding of the smoking-induced molecular alterations that contribute to the pathogenesis of lung adenocarcinoma.