The inhibitor of differentiation-1 (Id1) enables lung cancer liver colonization through activation of an EMT program in tumor cells and establishment of the pre-metastatic niche

Cancer Lett. 2017 Aug 28;402:43-51. doi: 10.1016/j.canlet.2017.05.012. Epub 2017 May 24.

Abstract

Id1 promotes carcinogenesis and metastasis, and predicts prognosis of non-small cell lung cancer (NSCLC)-adenocarcionoma patients. We hypothesized that Id1 may play a critical role in lung cancer colonization of the liver by affecting both tumor cells and the microenvironment. Depleted levels of Id1 in LLC (Lewis lung carcinoma cells, LLC shId1) significantly reduced cell proliferation and migration in vitro. Genetic loss of Id1 in the host tissue (Id1-/- mice) impaired liver colonization and increased survival of Id1-/- animals. Histologically, the presence of Id1 in tumor cells of liver metastasis was responsible for liver colonization. Microarray analysis comparing liver tumor nodules from Id1+/+ mice and Id1-/- mice injected with LLC control cells revealed that Id1 loss reduces the levels of EMT-related proteins, such as vimentin. In tissue microarrays containing 532 NSCLC patients' samples, we found that Id1 significantly correlated with vimentin and other EMT-related proteins. Id1 loss decreased the levels of vimentin, integrinβ1, TGFβ1 and snail, both in vitro and in vivo. Therefore, Id1 enables both LLC and the host microenvironment for an effective liver colonization, and may represent a novel therapeutic target to avoid NSCLC liver metastasis.

Keywords: Epithelial to mesenchymal transition; Id1; Liver colonization; Lung cancer; Vimentin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / metabolism*
  • Carcinoma, Lewis Lung / secondary
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / secondary
  • Cell Line, Tumor
  • Cell Movement*
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inhibitor of Differentiation Protein 1 / drug effects
  • Inhibitor of Differentiation Protein 1 / genetics
  • Inhibitor of Differentiation Protein 1 / metabolism*
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / secondary
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism
  • Time Factors
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Tumor Burden
  • Tumor Microenvironment*
  • Vimentin / genetics
  • Vimentin / metabolism

Substances

  • ID1 protein, human
  • Idb1 protein, mouse
  • Inhibitor of Differentiation Protein 1
  • Integrin beta1
  • Snail Family Transcription Factors
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • Vimentin