Regulation of PA200 in lung cancer
2021
Lung cancer is the leading cause of death among all cancer types with the most common incidence and mortality rates. The proteasome is a well-identified therapeutic target for cancer treatment. It acts as the main protein degradation system in the cell and degrades key mediators of cell growth, migration and survival. In this study, we analyzed non-tumorous and tumor tissues of patients suffering from different types of lung cancers. We observed significant upregulation of proteasome activator 200 (PA200) in tumor tissues compared to non-tumor lung samples of the same patient (Mann-Whitney U test, n=6). We also analyzed tumor tissue sections of lung cancer patients by immunohistochemistry and showed that PA200 was strongly induced in cancer cells. However, neither tumor stroma nor necrotic areas indicated expression of the activator. Importantly, PA200 is significantly increased in lung adenocarcinoma (LUAD), squamous cell lung cancer (SQCLC) compared to small cell lung cancer (SCLC) and correlated with significantly diminished survival in non-small cell lung cancer patients. Silencing of PA200 in the lung adenoma cell line A549 resulted in concerted downregulation of invasion, proliferation and metastasis-related gene expression. Our future experiments will focus on the function of PA200 in lung cancer cell growth, migration and invasion using CRISPR/Cas9 PA200 depleted A549 and H1299 cell lines. We will investigate the cellular function of modified PA200/proteasome complexes by analyzing RNA and protein signatures via RNA sequencing and mass spectrometry, respectively. We will use the power of functional assays (migration and invasion assay, colony formation assay) and address the functional role of PA200 as an oncogenic regulator in lung tumor growth and metastasis in vitro.
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