The putative PAX8/PPARγ fusion oncoprotein exhibits partial tumor suppressor activity through Up-regulation of Micro-RNA-122 and dominant-negative PPARγ activity

Honey V. Reddi, Pranathi Madde, Dragana Milosevic, Jennifer S. Hackbarth, Alicia Algeciras-Schimnich, Bryan Mciver, Stefan K.G. Grebe, Norman L. Eberhardt

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

In vitro studies have demonstrated that the PAX8/PPARγ fusion protein (PPFP), which occurs frequently in follicular thyroid carcinomas (FTC), exhibits oncogenic activity. However, paradoxically, a meta-analysis of extant tumor outcome studies indicates that 68% of FTC-expressing PPFP are minimally invasive compared to only 32% of those lacking PPFP (χ2 = 6.86, P = 0.008), suggesting that PPFP favorably impacts FTC outcomes. In studies designed to distinguish benign thyroid neoplasms from thyroid carcinomas, the previously identified tumor suppressor miR-122, a major liver micro-RNA (miR) that is decreased in hepatocellular carcinoma, was increased 8.9-fold (P < 0.05) in all FTC versus normal, 9.2-fold in FTC versus FA (P < 0.05), and 16.8-fold (P < 0.001) in FTC + PPFP versus FTC - PPFP. Constitutive expression of PPFP in the FTC-derived cell line WRO (WRO-PPFP) caused a 5-fold increase of miR-122 expression (P < 0.05) and a striking 5.1-fold reduction (P < 0.0001) in tumor progression compared to WRO-vector cells in a mouse xenograft model. Constitutive expression of either miR-122 or a dominant-negative PPARγ mutant in WRO cells was less effective than PPFP at inhibiting xenograft tumor progression (1.8-fold [P < 0.001] and 1.7-fold [P < 0.03], respectively). PPFP-induced up-regulation of miR-122 expression was independent of its known dominant-negative PPARγ activity. Up-regulation of miR-122 negatively regulates ADAM-17, a known downstream target, in thyroid cells, suggesting an antiangiogenic mechanism in thyroid carcinoma. This latter inference is directly supported by reduced CD-31 expression in WRO xenografts expressing PPFP, miR-122, and DN-PPARγ. We conclude that, in addition to its apparent oncogenic potential in vitro, PPFP exhibits paradoxical tumor suppressor activity in vivo, mediated by multiple mechanisms including up-regulation of miR-122 and dominant-negative inhibition of PPARγ activity.

Original languageEnglish (US)
Pages (from-to)46-55
Number of pages10
JournalGenes and Cancer
Volume2
Issue number1
DOIs
StatePublished - Jan 1 2011

Keywords

  • Follicular thyroid carcinoma
  • Fusion protein
  • Mir-122
  • Pax8/pparγ
  • Tumor suppressor

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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