Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

Nat Commun. 2014 Dec 1;5:5660. doi: 10.1038/ncomms6660.

Abstract

Ras pathway mutation is frequent in carcinomas where it induces expression of the transcriptional repressor ZEB1. Although ZEB1 is classically linked to epithelial-mesenchymal transition and tumour metastasis, it has an emerging second role in generation of cancer-initiating cells. Here we show that Ras induction of ZEB1 is required for tumour initiation in a lung cancer model, and we link this function to repression Pten, whose loss is critical for emergence of cancer-initiating cells. These two roles for ZEB1 in tumour progression can be distinguished by their requirement for different levels of ZEB1. A lower threshold of ZEB1 is sufficient for cancer initiation, whereas further induction is necessary for tumour metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adenoma / genetics*
  • Adenoma / pathology
  • Animals
  • Cell Transformation, Neoplastic / genetics*
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mice
  • Neoplasm Metastasis
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • RNA, Messenger / metabolism*
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • RNA, Messenger
  • ZEB1 protein, mouse
  • Zinc Finger E-box-Binding Homeobox 1
  • Phosphatidylinositol 3-Kinase
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)