CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • December 2, 2019

Research

keywords

  • Carcinoma, Non-Small-Cell Lung
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • I-kappa B Kinase
  • Lung Neoplasms

Identity

PubMed Central ID

  • PMC6892436

Scopus Document Identifier

  • 85076156766

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2013.03.012

PubMed ID

  • 31792060

Additional Document Info

volume

  • 2

issue

  • 6