Novel mechanisms of oncogenic transformation in lung cancer

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More people in the US die from lung cancer than from breast, prostate and colon cancer combined. Specific oncogenes, such as the growth factor signaling GTPase KRAS, are mutated and constitutively active in lung cancers. Although it is clear oncogenic proteins can drive lung cancer development, there is incomplete understanding of the molecular and genetic events that result in this process and in the initiation and progression of lung cancers. microRNA (miRNA), non-coding RNA that regulate protein expression, have been linked to cellular processes involved in tumor development and progression. We postulated that specific miRNA that are overexpressed in lung cancer may function as oncogenes themselves or cooperate with known oncogenes in the initiation of this malignancy. To determine whether specific miRNA have an oncogenic role in lung adenocarcinoma, the most common lung cancer, we investigated miRNA expression. Altered levels of specific miRNA were detected in lung adenocarcinoma, and one particular miRNA was overexpressed in a panel of lung adenocarcinoma cells lines that also contained activating mutations of KRAS. Notably, elevated levels of this miRNA were detected in human lung adenocarcinoma patient samples and this correlated with disease stage. Overexpression of this miRNA in untransformed human lung epithelial cells resulted in increased proliferation and anchorage-independent growth. Inhibition of this miRNA in human lung adenocarcinoma cells suppressed proliferation and overexpression induced tumor formation in a xenograft model. Importantly, in a novel, newly generated mouse model, inducible expression of this miRNA in the lungs rapidly led to hyperplasia and adenoma development. We have also identified multiple negative regulators of RAS pathway signaling as targets of this miRNA. Therefore, we hypothesize this miRNA is a novel driver of lung adenocarcinoma initiation through modulation of the RAS oncogenic signaling pathway and that it cooperates with mutant KRAS in lung cancer development. We propose to test this hypothesis with three Specific Aims. In Aim 1, we will use the novel lung specific inducible miRNA mouse to evaluate the effects of increased expression of this miRNA on lung cancer initiation and its contribution to mutant KRAS-driven lung cancer. In Aim 2, we will investigate the negative regulators of the oncogenic RAS pathway as targets of the specific miRNA, and we will identify novel targets that contribute to early and late changes in the lung during adenocarcinoma initiation and progression. In Aim 3, we will determine the genetic mutations in human lung cancer and the signaling pathways that regulate the expression of this miRNA. The integration of mouse models, patient samples, molecular biology, biochemistry, and cell biology proposed in this application will significantly increase understanding of the contribution of miRNA to lung adenocarcinoma and the molecular events that lead to the initiation of this deadly disease. Results from these studies are also likely to identify novel therapeutic targets and diagnostic and prognostic markers for lung adenocarcinoma.
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