First Author | Chavdoula E | Year | 2019 |
Journal | Life Sci Alliance | Volume | 2 |
Issue | 6 | PubMed ID | 31792060 |
Mgi Jnum | J:286960 | Mgi Id | MGI:6391761 |
Doi | 10.26508/lsa.201900460 | Citation | Chavdoula E, et al. (2019) CHUK/IKK-alpha loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation. Life Sci Alliance 2(6) |
abstractText | Through the progressive accumulation of genetic and epigenetic alterations in cellular physiology, non-small-cell lung cancer (NSCLC) evolves in distinct steps involving mutually exclusive oncogenic mutations in K-Ras or EGFR along with inactivating mutations in the p53 tumor suppressor. Herein, we show two independent in vivo lung cancer models in which CHUK/IKK-alpha acts as a major NSCLC tumor suppressor. In a novel transgenic mouse strain, wherein IKKalpha ablation is induced by tamoxifen (Tmx) solely in alveolar type II (AT-II) lung epithelial cells, IKKalpha loss increases the number and size of lung adenomas in response to the chemical carcinogen urethane, whereas IKK-beta instead acts as a tumor promoter in this same context. IKKalpha knockdown in three independent human NSCLC lines (independent of K-Ras or p53 status) enhances their growth as tumor xenografts in immune-compromised mice. Bioinformatics analysis of whole transcriptome profiling followed by quantitative protein and targeted gene expression validation experiments reveals that IKKalpha loss can result in the up-regulation of activated HIF-1-alpha protein to enhance NSCLC tumor growth under hypoxic conditions in vivo. |