NF-κB regulates mesenchymal transition for the induction of non-small cell lung cancer initiating cells. Academic Article uri icon

Overview

abstract

  • The epithelial-to-mesenchymal transition (EMT) is a de-differentiation process that has been implicated in metastasis and the generation of cancer initiating cells (CICs) in solid tumors. To examine EMT in non-small cell lung cancer (NSCLC), we utilized a three dimensional (3D) cell culture system in which cells were co-stimulated with tumor necrosis factor alpha (TNF) and transforming growth factor beta (TGFβ). NSCLC spheroid cultures display elevated expression of EMT master-switch transcription factors, TWIST1, SNAI1/Snail1, SNAI2/Slug and ZEB2/Sip1, and are highly invasive. Mesenchymal NSCLC cultures show CIC characteristics, displaying elevated expression of transcription factors KLF4, SOX2, POU5F1/Oct4, MYCN, and KIT. As a result, these putative CIC display a cancer "stem-like" phenotype by forming lung metastases under limiting cell dilution. The pleiotropic transcription factor, NF-κB, has been implicated in EMT and metastasis. Thus, we set out to develop a NSCLC model to further characterize the role of NF-κB activation in the development of CICs. Here, we demonstrate that induction of EMT in 3D cultures results in constitutive NF-κB activity. Furthermore, inhibition of NF-κB resulted in the loss of TWIST1, SNAI2, and ZEB2 induction, and a failure of cells to invade and metastasize. Our work indicates that NF-κB is required for NSCLC metastasis, in part, by transcriptionally upregulating master-switch transcription factors required for EMT.

publication date

  • July 30, 2013

Research

keywords

  • Carcinoma, Non-Small-Cell Lung
  • Cell Transformation, Neoplastic
  • Epithelial-Mesenchymal Transition
  • Lung Neoplasms
  • NF-kappa B

Identity

PubMed Central ID

  • PMC3728367

Scopus Document Identifier

  • 84880989513

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0014593

PubMed ID

  • 23935876

Additional Document Info

volume

  • 8

issue

  • 7