All ETDs from UAB

Advisory Committee Chair

Mick D Edmonds

Advisory Committee Members

John M Parant

Douglas R Hurst

Matthew S Alexander

Robert S Welner

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Lung cancer is the leading cause of cancer-related death both in the United Statesand the world. While several genetic drivers of lung cancer have been identified, major improvements in patient outcome are lacking, highlighting the need to further understand the genetic and molecular mechanisms of this disease. The microRNA miR-31 has been implicated in oncogenesis in a variety of cancer types, and prior data from our laboratory has shown it to be overexpressed in human lung adenocarcinoma tumors compared to normal lung, high miR-31 levels correlate with decreased patient survival, and overexpression of miR-31 alone in the mouse lung epithelium initiates lung tumorigenesis and adenocarcinoma development. These data indicate that miR-31 could be a potentially important therapeutic target for lung cancer. We evaluated the effects of long-term miR-31 knockdown in human lung adenocarcinoma cell lines using in vitro and in vivo assays of cell and tumor growth. Consistently, loss of miR-31 slowed the growth of these cells. We determined that loss of miR-31 allows the reactivation of several negative regulators of RAS/MAPK signaling. Given these cells were still capable of forming tumors in vivo and loss of miR-31 did not completely obliterate their growth, we investigated compensatory mechanisms of growth in these cells and identified a novel pathway which appears to drive miR-31 expression in lung adenocarcinoma and could be targeted in combination to further reduce the growth of lung adenocarcinoma cells. Expanding upon these studies, it has been well established that miRNA display tissue-specific functions, and miR-31 itself has been shown to have disparate functions in different cancer types, acting as an oncogene in some tissues while a tumor suppressor in others. We therefore sought to examine the role of miR-31 across the spectrum of lung cancer types. We demonstrated that miR-31 is overexpressed in specific subtypes, its overexpression results in unique oncogenic phenotypes, and it alters distinct cellular signaling cascades in each subtype. Our results demonstrate that miR-31 may be a viable therapeutic target across the histological spectrum of lung cancer, and we identify additional pathways in lung adenocarcinoma that could be targeted in combination.



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