RT Journal Article
SR Electronic
T1 CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900460
DO 10.26508/lsa.201900460
VO 2
IS 6
A1 Chavdoula, Evangelia
A1 Habiel, David M
A1 Roupakia, Eugenia
A1 Markopoulos, Georgios S
A1 Vasilaki, Eleni
A1 Kokkalis, Antonis
A1 Polyzos, Alexander P
A1 Boleti, Haralabia
A1 Thanos, Dimitris
A1 Klinakis, Apostolos
A1 Kolettas, Evangelos
A1 Marcu, Kenneth B
YR 2019
UL http://www.life-science-alliance.org/content/2/6/e201900460.abstract
AB 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-α acts as a major NSCLC tumor suppressor. In a novel transgenic mouse strain, wherein IKKα ablation is induced by tamoxifen (Tmx) solely in alveolar type II (AT-II) lung epithelial cells, IKKα loss increases the number and size of lung adenomas in response to the chemical carcinogen urethane, whereas IKK-β instead acts as a tumor promoter in this same context. IKKα 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 IKKα loss can result in the up-regulation of activated HIF-1-α protein to enhance NSCLC tumor growth under hypoxic conditions in vivo.