Transcript profiling identifies iqgap2(-/-) mouse as a model for advanced human hepatocellular carcinoma

PLoS One. 2013 Aug 12;8(8):e71826. doi: 10.1371/journal.pone.0071826. eCollection 2013.

Abstract

It is broadly accepted that genetically engineered animal models do not always recapitulate human pathobiology. Therefore identifying best-fit mouse models of human cancers that truly reflect the corresponding human disease is of vital importance in elucidating molecular mechanisms of tumorigenesis and developing preventive and therapeutic approaches. A new hepatocellular carcinoma (HCC) mouse model lacking a novel putative tumor suppressor IQGAP2 has been generated by our laboratory. The aim of this study was to obtain the molecular signature of Iqgap2(-/-) HCC tumors and establish the relevance of this model to human disease. Here we report a comprehensive transcriptome analysis of Iqgap2(-/-) livers and a cross-species comparison of human and Iqgap2(-/-) HCC tumors using Significance Analysis of Microarray (SAM) and unsupervised hierarchical clustering analysis. We identified the Wnt/β-catenin signaling pathway as the top canonical pathway dysregulated in Iqgap2(-/-) livers. We also demonstrated that Iqgap2(-/-) hepatic tumors shared genetic signatures with HCC tumors from patients with advanced disease as evidenced by a 78% mouse-to-human microarray data set concordance rate with 117 out of 151 identified ortholog genes having similar expression profiles across the two species. Collectively, these results indicate that the Iqgap2 knockout mouse model closely recapitulates human HCC at the molecular level and supports its further application for the study of this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Cell Transformation, Neoplastic / genetics
  • Cluster Analysis
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling*
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Staging
  • Reproducibility of Results
  • Signal Transduction
  • Transcriptome
  • Wnt Signaling Pathway
  • ras GTPase-Activating Proteins / deficiency*
  • ras GTPase-Activating Proteins / genetics
  • ras GTPase-Activating Proteins / metabolism

Substances

  • IQGAP2 protein, human
  • Iqgap2 protein, mouse
  • ras GTPase-Activating Proteins

Grant support

This research was supported by the Research Scholar Grant (RSG-09-033-01-CSM) from the American Cancer Society to VAS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.