Author of

• 12211

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  MO15 - Novel Genes and Pathways (ID 89)

  • Event: WCLC 2013
  • Type: Mini Oral Abstract Session
  • Track: Biology
  • Presentations: 1
  • Moderators:Y. Ohe, G. Reid
  • Coordinates: 10/29/2013, 16:15 - 17:45, Parkside Ballroom A, Level 1

  • 12215

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    MO15.04 - Loss of Tumor Suppressor Hic1 Accelerates the Progression of Lung Adenocarcinoma Induced by Oncogenic KRas (ID 2655)

    16:30 - 16:35  |  Author(s): A. Mudiyanselage
    • Abstract
    • Presentation
    • Slides

    Background
    Hypermethylated in Cancer-1 (Hic1) is a novel tumour suppressor gene that is frequently epigenetically silenced in adult tumours. In non-small cell lung cancer (NSCLC), loss of Hic1 expression is associated with reduced patient survival, suggesting reduced Hic1 expression is associated with malignant progression of NSCLC. However, whether Hic1 silencing is causal in lung cancer is not known. Hic1 is a transcriptional repressor that can regulate p53 function by repressing the expression of SIRT1, a class III histone deacetylase. We therefore hypothesized that loss of Hic1 function could cooperate with an oncogenic mutation in KRas (KRasG12D) to promote lung cancer initiation and/or progression in a similar fashion to genetic deletion of p53.

    Methods
    To address this question, we used a conditional genetic mouse model of lung adenocarcinoma in which administration of recombinant adenovirus expressing Cre can trigger recombination at loxP sites. When virus is administered to mice heterozygous for a conditional KRasG12D allele, mice develop multiple lung adenomas that progress to adenocarcinomas over 8-12 weeks. To test the function of Hic1 as a tumour suppressor, we created a conditional knockout mouse allele (Hic1[lox]), in which loxP sites flank the single coding exon.

    Results
    Following administration of Cre adenovirus, mice carrying the KRasG12D allele and homozygous for the Hic1[lox] allele, developed aggressive lung adenocarcinomas at a markedly accelerated rate and had a significantly shortened survival compared to KRasG12D animals. Remarkably, these tumours exhibited a highly malignant phenotype with highly proliferative micropapillary and pleomorphic features.

    Conclusion
    These data show that loss of Hic1 function can substitute for p53 mutation as a cooperating event in lung adenocarcinoma progression. Since the highly aggressive phenotype of KRasG12D/Hic1[lox/lox] lung tumours has not been reported in the KRasG12D/p53[lox/lox] lung cancer model, we speculate that Hic1 may function as a tumour suppressor beyond the regulation of p53 through Sirt1.

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