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

Fingerprint

Insulin-Like Growth Factor II
Cell Proliferation
Neoplasms
Aberrant Crypt Foci
Azoxymethane
Epigenomics
Genes
IGF Type 2 Receptor
Microfluidics
Insulin Receptor
Chemoprevention
Mutagenesis
Signal Transduction
Colon
Carcinogenesis
Alleles
Mothers
Gene Expression

Keywords

  • Akt
  • Cancer
  • Chemoprevention
  • Epigenetics
  • Signal transduction

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. / Kaneda, Atsushi; Wang, Chiaochun J.; Cheong, Raymond; Timp, Winston; Onyango, Patrick; Wen, Bo; Iacobuzio-Donahue, Christine A.; Ohlsson, Rolf; Andraos, Rita; Pearson, Mark A.; Sharov, Alexei A.; Longo, Dan L.; Ko, Minoru S H; Levchenko, Andre; Feinberg, Andrew P.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 52, 26.12.2007, p. 20926-20931.

Research output: Contribution to journalArticle

Kaneda, A, Wang, CJ, Cheong, R, Timp, W, Onyango, P, Wen, B, Iacobuzio-Donahue, CA, Ohlsson, R, Andraos, R, Pearson, MA, Sharov, AA, Longo, DL, Ko, MSH, Levchenko, A & Feinberg, AP 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, vol. 104, no. 52, pp. 20926-20931. https://doi.org/10.1073/pnas.0710359105
Kaneda, Atsushi ; Wang, Chiaochun J. ; Cheong, Raymond ; Timp, Winston ; Onyango, Patrick ; Wen, Bo ; Iacobuzio-Donahue, Christine A. ; Ohlsson, Rolf ; Andraos, Rita ; Pearson, Mark A. ; Sharov, Alexei A. ; Longo, Dan L. ; Ko, Minoru S H ; Levchenko, Andre ; Feinberg, Andrew P. / Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 52. pp. 20926-20931.
@article{bcf5fdfa20a6474f99db6b31c9903626,
title = "Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk",
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.",
keywords = "Akt, Cancer, Chemoprevention, Epigenetics, Signal transduction",
author = "Atsushi Kaneda and Wang, {Chiaochun J.} and Raymond Cheong and Winston Timp and Patrick Onyango and Bo Wen and Iacobuzio-Donahue, {Christine A.} and Rolf Ohlsson and Rita Andraos and Pearson, {Mark A.} and Sharov, {Alexei A.} and Longo, {Dan L.} and Ko, {Minoru S H} and Andre Levchenko and Feinberg, {Andrew P}",
year = "2007",
month = "12",
day = "26",
doi = "10.1073/pnas.0710359105",
language = "English (US)",
volume = "104",
pages = "20926--20931",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "52",

}

TY - JOUR

T1 - Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk

AU - Kaneda, Atsushi

AU - Wang, Chiaochun J.

AU - Cheong, Raymond

AU - Timp, Winston

AU - Onyango, Patrick

AU - Wen, Bo

AU - Iacobuzio-Donahue, Christine A.

AU - Ohlsson, Rolf

AU - Andraos, Rita

AU - Pearson, Mark A.

AU - Sharov, Alexei A.

AU - Longo, Dan L.

AU - Ko, Minoru S H

AU - Levchenko, Andre

AU - Feinberg, Andrew P

PY - 2007/12/26

Y1 - 2007/12/26

N2 - 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.

AB - 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.

KW - Akt

KW - Cancer

KW - Chemoprevention

KW - Epigenetics

KW - Signal transduction

UR - http://www.scopus.com/inward/record.url?scp=38049170553&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38049170553&partnerID=8YFLogxK

U2 - 10.1073/pnas.0710359105

DO - 10.1073/pnas.0710359105

M3 - Article

VL - 104

SP - 20926

EP - 20931

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 52

ER -