Chronic obstructive pulmonary disease (COPD) is a longterm lung disease characterized by irreversible lung damage resulting in airflow limitation, abnormal permanent airspace enlargement, and emphysema. Cigarette smoking is the major cause of COPD with 15% to 30% of smokers developing either disease. About 50% to 80% of patients with lung cancer have preexisting COPD and smokers who have COPD are at an increased risk for developing lung cancer. Therefore, COPD is considered an independent risk for lung cancer, even after adjusting for smoking. A crucial early event in carcinogenesis is the induction of the genomic instability through alterations in the mitotic spindle apparatus. To date, the underlying mechanism by which COPD contributes to lung cancer risk is unclear. We hypothesized that tobacco smoke carcinogens induce mitotic spindle apparatus abnormalities and alter expression of crucial genes leading to increased genomic instability and ultimately tumorigenesis. To test our hypothesis, we assessed the genotoxic effects of a potent tobacco-smoke carcinogen [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, (NNK)] on bronchial epithelial cells from patients with COPD and normal bronchial epithelial cells and identified genes associated with mitotic spindle defects and chromosome missegregation that also overlap with lung cancer. Our results indicate that exposure to NNK leads to a significantly altered spindle orientation, centrosome amplification, and chromosome misalignment in COPD cells as compared with normal epithelial cells. In addition, we identified several genes (such as AURKA, AURKB, and MAD2L2) that were upregulated and overlap with lung cancer suggesting a potential common pathway in the transition from COPD to lung cancer.

The current study tested expression and potential function of circular RNA ecto-5'-nucleotidase (circNT5E) in human non-small cell lung cancer (NSCLC). We show that circNT5E levels are significantly elevated in human NSCLC tissues and cells, correlating with downregulation of its potential targets, miR-134, miR-422a and miR-338. In A549 and primary NSCLC cells, circNT5E shRNA inhibited cancer cell growth, proliferation and migration, whiling inducing apoptosis activation. Conversely, ectopic circNT5E overexpression promoted A549 cell progression in vitro. miR-134 is the primary target of circNT5E in lung cancer cells. RNA-Pull down assay in A549 cells confirmed the direct association between biotinylated-miR-134 and circNT6E. miR-134 levels were significantly increased in circNT5E-silenced A549 cells, but reduced with circNT5E overexpression. Forced overexpression of miR-134 mimicked circNT5E shRNA-induced actions, inhibiting NSCLC cell growth and proliferation. In contrast, miR-134 inhibition largely attenuated circNT5E shRNA-induced anti-NSCLC cell activity. Importantly, circNT5E shRNA was ineffective in miR-134overexpressed A549 cells. Collectively, circNT5E promotes human NSCLC cell progression possibly by sponging miR-134.

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