Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk

Atsushi Kaneda, Chiaochun J. Wang, Raymond Cheong, Winston Timp, Patrick Onyango, Bo Wen, Christine A. Iacobuzio-Donahue, Rolf Ohlsson, Rita Andraos, Mark A. Pearson, Alexei A. Sharov, Dan L. Longo, Minoru S.H. Ko, Andre Levchenko, Andrew P. Feinberg

Research output: Contribution to journalArticle

Abstract

Loss of imprinting (LOI) of the insulin-like growth factor-II gene (IGF2), leading to abnormal activation of the normally silent maternal allele, is a common human epigenetic population variant associated with a 5-fold increased frequency of colorectal neoplasia. Here, we show first that LOI leads specifically to increased expression of proliferation-related genes in mouse intestinal crypts. Surprisingly, LOI(+) mice also have enhanced sensitivity to IGF-II signaling, not simply increased IGF-II levels, because in vivo blockade with NVP-AEW541, a specific inhibitor of the IGF-II signaling receptor, showed reduction of proliferation-related gene expression to levels half that seen in LOI(-) mice. Signal transduction assays in microfluidic chips confirmed this enhanced sensitivity with marked augmentation of Akt/PKB signaling in LOI(+) cells at low doses of IGF-II, which was reduced in the presence of the inhibitor to levels below those found in LOI(-) cells, and was associated with increased expression of the IGF1 and insulin receptor genes. We exploited this increased IGF-II sensitivity to develop an in vivo chemopreventive strategy using the azoxymethane (AOM) mutagenesis model. LOI(+) mice treated with AOM showed a 60% increase in premalignant aberrant crypt foci (ACF) formation over LOI(-) mice. In vivo IGF-II blockade with NVP-AEW541 abrogated this effect, reducing ACF to a level 30% lower even than found in exposed LOI(-) mice. Thus, LOI increases cancer risk in a counterintuitive way, by increasing the sensitivity of the IGF-II signaling pathway itself, providing a previously undescribed epigenetic chemoprevention strategy in which cells with LOI are "IGF-II addicted" and undergo reduced tumorigenesis in the colon upon IGF-II pathway blockade.

Original languageEnglish (US)
Pages (from-to)20926-20931
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number52
DOIs
StatePublished - Dec 26 2007

Keywords

  • Akt
  • Cancer
  • Chemoprevention
  • Epigenetics
  • Signal transduction

ASJC Scopus subject areas

  • General

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    Kaneda, A., Wang, C. J., Cheong, R., Timp, W., Onyango, P., Wen, B., Iacobuzio-Donahue, C. A., Ohlsson, R., Andraos, R., Pearson, M. A., Sharov, A. A., Longo, D. L., Ko, M. S. H., Levchenko, A., & Feinberg, A. P. (2007). Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. Proceedings of the National Academy of Sciences of the United States of America, 104(52), 20926-20931. https://doi.org/10.1073/pnas.0710359105