Search: onr:"swepub:oai:DiVA.org:uu-113042" >
Enhanced sensitivit...
Enhanced sensitivity to IGF-II signalling links loss of imprinting of IGF2 to increased cell proliferation and tumour risk
-
Kaneda, Atsushi (author)
-
Wang, Chiaochun J. (author)
-
Cheong, Raymond (author)
-
show more...
-
Timp, Winston (author)
-
Onyango, Patrick (author)
-
Wen, Bo (author)
-
Lacobuzio-Donahuel, Christine A. (author)
-
- Ohlsson, Rolf (author)
- Karolinska Institutet,Uppsala universitet,Institutionen för fysiologi och utvecklingsbiologi
-
Andraos, Rita (author)
-
Pearson, Mark A. (author)
-
Sharov, Alexei A. (author)
-
Longol, Dan L. (author)
-
Ko, Minoru S. H. (author)
-
Levchenko, Andre (author)
-
Feinberg, Andrew P. (author)
-
show less...
-
(creator_code:org_t)
- 2007-12-26
- 2007
- English.
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:52, s. 20926-20931
- Related links:
-
http://www.pnas.org/...
-
show more...
-
http://www.pnas.org/...
-
https://urn.kb.se/re...
-
https://doi.org/10.1...
-
http://kipublication...
-
show less...
Abstract
Subject headings
Close
- 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.
Subject headings
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
Keyword
- Akt
- cancer
- chemoprevention
- epigenetics
- signal transduction
- Biology
- Biologi
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database
- By the author/editor
-
Kaneda, Atsushi
-
Wang, Chiaochun ...
-
Cheong, Raymond
-
Timp, Winston
-
Onyango, Patrick
-
Wen, Bo
-
show more...
-
Lacobuzio-Donahu ...
-
Ohlsson, Rolf
-
Andraos, Rita
-
Pearson, Mark A.
-
Sharov, Alexei A ...
-
Longol, Dan L.
-
Ko, Minoru S. H.
-
Levchenko, Andre
-
Feinberg, Andrew ...
-
show less...
- About the subject
-
- NATURAL SCIENCES
-
NATURAL SCIENCES
-
and Biological Scien ...
- Articles in the publication
-
Proceedings of t ...
- By the university
-
Uppsala University
-
Karolinska Institutet