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Simultaneous targeted activation of Notch1 and Vhl-disruption in the kidney proximal epithelial tubular cells in mice

Johansson, Elinn LU ; Rönö, Birgitte LU ; Johansson, Martin LU ; Lindgren, David LU ; Möller, Christina LU ; Axelson, Håkan LU and Smith, Emma M K LU (2016) In Scientific Reports 6.
Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, representing approximately 75% of all renal neoplasms. ccRCC is known to be strongly associated with silencing of the von Hippel Lindau (VHL) tumor suppressor gene, yet VHL deficiency alone does not seem to be sufficient to drive the oncogenic transformation of normal renal epithelium and induce renal tumorigenesis. We, and others, have previously suggested that constitutive activation of the Notch signaling pathway, alongside with VHL loss, contribute to the oncogenic features of ccRCC. Here we report a prevailing hyperactivation of the Notch1 receptor in human ccRCC relative to the healthy counterpart. To explore the consequences of the elevated... (More)

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, representing approximately 75% of all renal neoplasms. ccRCC is known to be strongly associated with silencing of the von Hippel Lindau (VHL) tumor suppressor gene, yet VHL deficiency alone does not seem to be sufficient to drive the oncogenic transformation of normal renal epithelium and induce renal tumorigenesis. We, and others, have previously suggested that constitutive activation of the Notch signaling pathway, alongside with VHL loss, contribute to the oncogenic features of ccRCC. Here we report a prevailing hyperactivation of the Notch1 receptor in human ccRCC relative to the healthy counterpart. To explore the consequences of the elevated Notch1 signaling observed in ccRCC patient material, we made use of a conditional mouse model based on concurrent ectopic expression of constitutively active Notch1 (NICD1) and deletion of the Vhl gene. Histological examination of the kidneys of the conditional mice demonstrate the existence of nests of dysplastic cells with a clear cytoplasm as a consequence of lipid accumulation, thus displaying a one important hallmark of human ccRCC.

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author
organization
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type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
6
pages
10 pages
publisher
Nature Publishing Group
external identifiers
  • Scopus:84981169851
  • WOS:000380882200001
ISSN
2045-2322
DOI
10.1038/srep30739
language
English
LU publication?
yes
id
25ec7f59-3b65-4f2d-a244-33feaa981c11
date added to LUP
2016-08-09 08:52:34
date last changed
2017-01-12 15:12:22
@article{25ec7f59-3b65-4f2d-a244-33feaa981c11,
  abstract     = {<p>Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, representing approximately 75% of all renal neoplasms. ccRCC is known to be strongly associated with silencing of the von Hippel Lindau (VHL) tumor suppressor gene, yet VHL deficiency alone does not seem to be sufficient to drive the oncogenic transformation of normal renal epithelium and induce renal tumorigenesis. We, and others, have previously suggested that constitutive activation of the Notch signaling pathway, alongside with VHL loss, contribute to the oncogenic features of ccRCC. Here we report a prevailing hyperactivation of the Notch1 receptor in human ccRCC relative to the healthy counterpart. To explore the consequences of the elevated Notch1 signaling observed in ccRCC patient material, we made use of a conditional mouse model based on concurrent ectopic expression of constitutively active Notch1 (NICD1) and deletion of the Vhl gene. Histological examination of the kidneys of the conditional mice demonstrate the existence of nests of dysplastic cells with a clear cytoplasm as a consequence of lipid accumulation, thus displaying a one important hallmark of human ccRCC.</p>},
  articleno    = {30739},
  author       = {Johansson, Elinn and Rönö, Birgitte and Johansson, Martin and Lindgren, David and Möller, Christina and Axelson, Håkan and Smith, Emma M K},
  issn         = {2045-2322},
  language     = {eng},
  month        = {08},
  pages        = {10},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Simultaneous targeted activation of Notch1 and Vhl-disruption in the kidney proximal epithelial tubular cells in mice},
  url          = {http://dx.doi.org/10.1038/srep30739},
  volume       = {6},
  year         = {2016},
}