GCIP functions as a tumor suppressor in non-small cell lung cancer by suppressing Id1-mediated tumor promotion

Oncotarget. 2014 Jul 15;5(13):5017-28. doi: 10.18632/oncotarget.2075.

Abstract

Grap2 and cyclin D1 interacting protein (GCIP) has been recognized as a putative tumor suppressor, but the molecular mechanisms underlying its anti-tumor properties remain undefined. Here, we report that GCIP is frequently downregulated in non-small cell lung cancer (NSCLC) tissues. Binding assays indicated that inhibitor of DNA binding/differentiation 1 (Id1) interacts with GCIP in the nucleus. Ectopic GCIP expression in the highly invasive NSCLC cell line, H1299, inhibited proliferation, colony formation, invasion and migration, and increased susceptibility to anticancer drugs. Conversely, silencing GCIP expression in the minimally invasive NSCLS cell line, A549, increased proliferation, colony formation, invasion, and migration in vitro, and increased survival and resistance to anticancer drugs. GCIP also suppresses tumorigenicity of NSCLC cells in vivo and GCIP suppresses NSCLC progression is mediated in part by interfering with Id1 signaling, which was confirmed in conditionally induced stable cell lines. In addition, GCIP downregulates the expression of Id1, and GCIP and Id1 are inversely expressed in NSCLC cell lines and specimens. Taken together, these results suggest that GCIP is a potential tumor suppressor in NSCLC and that suppression of Id1-mediated oncogenic properties may be a key mechanism by which GCIP can potently suppress NSCLC tumor progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Inhibitor of Differentiation Protein 1 / genetics
  • Inhibitor of Differentiation Protein 1 / metabolism*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microscopy, Confocal
  • Protein Binding
  • RNA Interference
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transplantation, Heterologous
  • Tumor Burden / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Antineoplastic Agents
  • CCNDBP1 protein, human
  • ID1 protein, human
  • Inhibitor of Differentiation Protein 1
  • Transcription Factors
  • Tumor Suppressor Proteins