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miR-200 MicroRNAs in Lung cancer metastasis

Institution: University of California, Berkeley
Investigator(s): Suifang Mao,
Award Cycle: 2019 (Cycle 30) Grant #: T30FT1019 Award: $191,832
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Lung cancer is the leading cause of cancer death worldwide, largely due to its highly aggressive and metastatic nature. Tobacco consumption is a major risk for lung cancer, contributing to 80% to 90% of lung cancer cases in the United States. In particular, long-term cigarette smoking leads to dysregulation of cellular processes and molecular network in airway epithelia, strongly promoting lung cancer initiation, progression and metastasis, and enhancing its mortality. While a lot of research has elucidated how smoking promote lung cancer initiation and progression, the cellular and molecular mechanism through which smoking negatively impacts lung cancer metastasis remains largely unknown. Multiple lines of evidence demonstrated that the exposure to cigarette smoke significantly alters the expression of non-coding RNAs, particularly microRNAs (miRNAs). Interestingly, our preliminary results suggest that some miRNAs that are strongly repressed by cigarette smoking act as key repressors for lung cancer metastasis. Hence, I hypothesize that cigarette smoking plays an essential role in promoting lung cancer metastasis, at least in part, by repressing specific miRNAs. miR-200 miRNAs are a family of five conserved miRNAs that are highly expressed in normal lung and gut epithelial cells. Multiple studies have demonstrated a marked miR-200 downregulation by exposures to cigarette smoke in human bronchial epithelia cells, sputum and serum. Downregulation of miR-200 is also observed in oral tumor when patients have a history of tobacco chewing/smoking. In our preliminary studies, a marked miR-200 decrease is not only observed in metastatic lung tumors in a mouse lung adenocarcinomas model, but also associated with poor patient survival in human lung adenocarcinoma patients. More importantly, miR-200 deficiency in a Kras-driven, p53 deficient lung adenocarcinoma model strongly promotes spontaneous lung cancer metastasis in vivo. Collectively, I hypothesize that miR-200 downregulation is likely to act downstream of cigarette smoking to promote lung cancer metastasis. Using mouse tumor models, genomics, cell and molecular biology approaches, I propose to elucidate the molecular mechanism underlying miR-200 downregulation by smoking, providing biomarker and therapeutic target for smoker lung cancer patients in diagnosis and treatment for metastatic lung adenocarcinoma.