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Leveraging transcriptomic regulation to understand, diagnose and intercept early lung cancer pathogenesis

Lung cancer is the leading cause of cancer death in the US, largely due to the lack of treatment options to intercept the progression of early lung cancers and methods to diagnose lung cancer at early stages. Prior studies indicated that the lack of immune surveillance is associated with the progression of bronchial premalignant lesions (PMLs) and the gene alterations in the nasal epithelium can be leveraged for the early detection of lung cancer. Yet, the regulatory mechanism of these gene expression alterations is still less understood. Thus, there are unmet needs to study the gene expression regulation for better disease management of early lung cancer, including further understanding the biology of early lung cancer development, identifying potential interception strategies, and improving the lung cancer diagnosis.
My dissertation addresses these challenges by investigating the transcriptional and post-transcriptional gene expression regulators, including transcription factors and microRNAs (miRNAs), to facilitate the understanding, interception, and diagnosis of early lung cancer. First, I explored the miRNA regulatory landscape to identify miRNA-gene regulatory relationships associated with bronchial PML progression and molecular subtypes. Using matched gene and microRNA expression profiles from patients with bronchial premalignant lesions, I identified epithelial miR-149-5p to be a key regulator of gene expression contributing to PML progression. By suppressing NLRC5, miR-149-5p inhibits MHC-I gene expression of epithelial cells, promoting early immune depletion and lesion progression. I also developed a novel statistical framework, Differential Regulation Analysis of miRNA (DReAmiR), that characterizes miRNA-mediated gene regulatory network rewiring across multiple groups from transcriptomic profiles, and identified regulatory network differences across PML molecular subtypes. Secondly, I investigated the alterations in the Hippo pathway to identify potential drug targets to intercept the progression of bronchial PMLs. I found that Hippo pathway effectors YAP/TAZ, together with transcription factors TEAD and TP63, cooperatively promote basal cell proliferation and repress signals associated with interferon responses and immune cell communication. Further in silico drug screening with external datasets identified small compounds that can reverse the direct regulated gene signature to potentially intercept bronchial PML progression. Lastly, I integrated miRNA and gene expression profiles in the nasal epithelium to distinguish malignant from benign indeterminate pulmonary nodules. I built an ensemble classifier consisting of nasal epithelial miRNA expression features, miRNA-gene top scoring pairs, and clinical features. The performance of the ensemble classifier exceeded that of the classifier built with clinical features alone.
Collectively, my thesis investigated the gene expression regulation mechanisms to facilitate the understanding, interception, and diagnosis of early lung cancer pathogenesis. / 2025-11-06T00:00:00Z
Date07 November 2023
CreatorsNing, Boting
ContributorsLenburg, Marc E., Beane-Ebel, Jennifer
Source SetsBoston University
Detected LanguageEnglish

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