MicroRNAs as modulators of the airway gener expression response to smoking and lung cancer

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. This high mortality rate results largely from the lack of effective tools to diagnose the disease at an early stage, when it is still curable. Smoking, particularly of cigarettes, is the main contributor to lung cancer. The molecular alterations caused by cigarette smoke are not limited to the lung, but rather constitute a "field of injury" throughout the entire respiratory tract that is exposed to the toxins. This "field of injury" occurs in healthy smokers and can precede the development of smoking-induced lung disease. Consistent with this idea our group has previously developed a gene expression-based biomarker in the cytologically normal bronchial epithelium that reflects an individual's physiologic response to smoking and distinguishes smokers with and without lung cancer. While the molecular alterations that characterize the field of injury have been extensively studied, the regulatory mechanisms responsible for driving these changes are not well understood. Here, I first show that smoking alters microRNA expression in the bronchial epithelium and in turn, these smoking-related microRNAs are responsible for modulating the gene expression changes that occur in response to tobacco exposure. Second, by studying differences in splicing between the nasal and bronchial epithelium, I demonstrate that a significantly alternatively spliced gene, Sfrs1, plays an important role in mediating splicing changes between these two tissues and in promoting site-specific gene expression responses to smoking through the regulation of miR-1Ob processing. Lastly, through the use of next-generation sequencing technology, we have identified a primate-specific microRNA, miR-4423, whose expression I show is largely restricted to the airway epithelium and may play a role in promoting the differentiation and/or maintenance of the airway. In addition, I show that miR-4423 expression is associated with lung cancer and its ectopic expression reduces anchorage-independent lung cancer cell growth. Together, this work significantly advances an understanding of the complex genomic networks that underlie the response to smoking in the airway epithelium and adds evidence to the notion that the "field of injury" concept can be leveraged to gain biological insights into the mechanism of smoking-induced lung disease.