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Increased Expression of the Very Low-Density Lipoprotein Receptor Mediates Lipid Accumulation in Clear-Cell Renal Cell Carcinoma

Sundelin, Jeanna Perman; Stahlman, Marcus; Lundqvist, Annika; Levin, Max; Parini, Paolo; Johansson, Martin LU and Boren, Jan (2012) In PLoS ONE 7(11).
Abstract
Clear-cell renal cell carcinoma (RCC) is, in most cases, caused by loss of function of the tumor suppressor gene von Hippel-Lindau, resulting in constitutive activation of hypoxia-inducible factor (HIF)-1 alpha and expression of hypoxia-induced genes in normoxic conditions. Clear-cell RCC cells are characterized histologically by accumulation of cholesterol, mainly in its ester form. The origin of the increased cholesterol remains unclear, but it is likely explained by an HIF-1 alpha-driven imbalance between cholesterol uptake and excretion. Here, we showed that expression of the very low-density lipoprotein receptor (VLDL-R) was significantly increased in clear-cell RCC human biopsies compared with normal kidney tissue. Partial knockdown... (More)
Clear-cell renal cell carcinoma (RCC) is, in most cases, caused by loss of function of the tumor suppressor gene von Hippel-Lindau, resulting in constitutive activation of hypoxia-inducible factor (HIF)-1 alpha and expression of hypoxia-induced genes in normoxic conditions. Clear-cell RCC cells are characterized histologically by accumulation of cholesterol, mainly in its ester form. The origin of the increased cholesterol remains unclear, but it is likely explained by an HIF-1 alpha-driven imbalance between cholesterol uptake and excretion. Here, we showed that expression of the very low-density lipoprotein receptor (VLDL-R) was significantly increased in clear-cell RCC human biopsies compared with normal kidney tissue. Partial knockdown of HIF-1 alpha in clear-cell RCC cells significantly reduced the VLDL-R expression, and knockdown of either HIF-1 alpha or VLDL-R reduced the increased lipid accumulation observed in these cells. We also showed increased uptake of fluorescently labeled lipoproteins in clear-cell RCC cells, which was significantly reduced by knockdown of HIF-1 alpha or VLDL-R. Taken together, our results support the concept that the pathological increase of HIF-1 alpha in clear-cell RCC cells upregulates VLDL-R, which mediates increased uptake and accumulation of lipids. These results explain the morphological characteristics of clear-cell RCC, and open up novel possibilities for detection and treatment of clear-cell RCC. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
7
issue
11
publisher
Public Library of Science
external identifiers
  • wos:000311333800009
  • scopus:84869856786
ISSN
1932-6203
DOI
10.1371/journal.pone.0048694
language
English
LU publication?
yes
id
f5eb7718-217f-49e9-ac5a-68a7127fb42b (old id 3372804)
date added to LUP
2013-02-01 07:01:04
date last changed
2017-06-11 04:01:30
@article{f5eb7718-217f-49e9-ac5a-68a7127fb42b,
  abstract     = {Clear-cell renal cell carcinoma (RCC) is, in most cases, caused by loss of function of the tumor suppressor gene von Hippel-Lindau, resulting in constitutive activation of hypoxia-inducible factor (HIF)-1 alpha and expression of hypoxia-induced genes in normoxic conditions. Clear-cell RCC cells are characterized histologically by accumulation of cholesterol, mainly in its ester form. The origin of the increased cholesterol remains unclear, but it is likely explained by an HIF-1 alpha-driven imbalance between cholesterol uptake and excretion. Here, we showed that expression of the very low-density lipoprotein receptor (VLDL-R) was significantly increased in clear-cell RCC human biopsies compared with normal kidney tissue. Partial knockdown of HIF-1 alpha in clear-cell RCC cells significantly reduced the VLDL-R expression, and knockdown of either HIF-1 alpha or VLDL-R reduced the increased lipid accumulation observed in these cells. We also showed increased uptake of fluorescently labeled lipoproteins in clear-cell RCC cells, which was significantly reduced by knockdown of HIF-1 alpha or VLDL-R. Taken together, our results support the concept that the pathological increase of HIF-1 alpha in clear-cell RCC cells upregulates VLDL-R, which mediates increased uptake and accumulation of lipids. These results explain the morphological characteristics of clear-cell RCC, and open up novel possibilities for detection and treatment of clear-cell RCC.},
  author       = {Sundelin, Jeanna Perman and Stahlman, Marcus and Lundqvist, Annika and Levin, Max and Parini, Paolo and Johansson, Martin and Boren, Jan},
  issn         = {1932-6203},
  language     = {eng},
  number       = {11},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Increased Expression of the Very Low-Density Lipoprotein Receptor Mediates Lipid Accumulation in Clear-Cell Renal Cell Carcinoma},
  url          = {http://dx.doi.org/10.1371/journal.pone.0048694},
  volume       = {7},
  year         = {2012},
}