Pluto Bioinformatics

GSE140432 (mouse): CHUK/IKKalpha loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation

Bulk RNA sequencing

During the natural progression of Non-small-cell lung cancer (NSCLC), tumor cells evolve progressively through the accumulation of mutations, some of which involve oncogenic (K-RAS, EGFR) or tumor suppressor (P53) genes. These mutations alter cell signaling pathways to promote tumor growth and survival in the tumor microenvironment. Herein we show that CHUK (IKK-alpha) acts as a prominent tumor suppressor in two independent NSCLC models.; Using a novel transgenic mouse strain, where IKK-alpha gene is ablated using tamoxifen in alveolar type II epithelial cells, loss of IKK-alpha increased the number and size of lung tumors in response to the chemical carcinogen urethane. Furthermore, IKK-alpha knock-down in three human NSCLC lines (showing independent K-Ras or p53 mutations and status) promoted their growth as xenografts in immunocompromised mice. Transcriptomic and functional studies of IKK-alpha knock-down tumors, relative to their wild type counterparts, suggested that the loss of IKK-alpha promoted the activation of HIF-1 alpha and higher tumor cell growth and survival under hypoxic conditions.; Together, these results suggest that IKK-alpha acts as a tumor suppressor by suppressing the activity of HIF-1 alpha and tumor cell growth/survival under hypoxic conditions. SOURCE: David Habiel (david.habiel@gmail.com) - Cedars-Sinai Medical Center