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Scavenger receptor BI promotes cytoplasmic accumulation of lipoproteins in clear-cell renal cell carcinoma


Velagapudi, Srividya; Schraml, Peter; Yalcinkaya, Mustafa; Bolck, Hella Anna; Rohrer, Lucia; Moch, Holger; von Eckardstein, Arnold (2018). Scavenger receptor BI promotes cytoplasmic accumulation of lipoproteins in clear-cell renal cell carcinoma. Journal of Lipid Research, 59(11):2188-2201.

Abstract

Clear cell renal cell carcinomas (ccRCC) are characterized by inactivation of von Hippel-Lindau (VHL) gene and intracellular lipid accumulation by unknown pathomechanism. The immunochemical analysis of 356 RCCs revealed high abundance of apolipoproteins apoA-I and apoB as well as scavenger receptor BI (SR-BI) in the clear cell RCC subtype. Given the characteristic loss of VHL function in ccRCC, we used VHL-defective and VHL-proficient cells to study the potential influence of VHL on lipoprotein uptake. VHL-defective patient-derived ccRCC cells and cell lines (786O and RCC4) showed enhanced uptake as well as less re-secretion and degradation of radio-iodinated high and low density lipoproteins (125I-HDL and 125I-LDL) compared to the VHL-proficient cells. The ccRCC cells showed enhanced VEGF and SR-BI expression compared to normal kidney epithelial cells. Uptake of 125I-HDL and 125I-LDL by patient-derived normal kidney epithelial cells as well as VHL-re-expressing ccRCC cell lines 786-O-VHL and RCC4-O-VHL cells was strongly enhanced by VEGF treatment. The knock-down of VEGF co-receptor neuropilin (NRP1) as well as blocking of SR-BI significantly reduced the uptake of lipoproteins into ccRCC cells in vitro. LDL stimulated proliferation of 786-O cells more potently than 786-O-VHL cells in a NRP1- and SR-BI- dependent manner. In conclusion, enhanced lipoprotein uptake due to increased activities of VEGF/NRP1 and SR-BI promotes lipid accumulation and proliferation of VHL-defective ccRCC cells.

Abstract

Clear cell renal cell carcinomas (ccRCC) are characterized by inactivation of von Hippel-Lindau (VHL) gene and intracellular lipid accumulation by unknown pathomechanism. The immunochemical analysis of 356 RCCs revealed high abundance of apolipoproteins apoA-I and apoB as well as scavenger receptor BI (SR-BI) in the clear cell RCC subtype. Given the characteristic loss of VHL function in ccRCC, we used VHL-defective and VHL-proficient cells to study the potential influence of VHL on lipoprotein uptake. VHL-defective patient-derived ccRCC cells and cell lines (786O and RCC4) showed enhanced uptake as well as less re-secretion and degradation of radio-iodinated high and low density lipoproteins (125I-HDL and 125I-LDL) compared to the VHL-proficient cells. The ccRCC cells showed enhanced VEGF and SR-BI expression compared to normal kidney epithelial cells. Uptake of 125I-HDL and 125I-LDL by patient-derived normal kidney epithelial cells as well as VHL-re-expressing ccRCC cell lines 786-O-VHL and RCC4-O-VHL cells was strongly enhanced by VEGF treatment. The knock-down of VEGF co-receptor neuropilin (NRP1) as well as blocking of SR-BI significantly reduced the uptake of lipoproteins into ccRCC cells in vitro. LDL stimulated proliferation of 786-O cells more potently than 786-O-VHL cells in a NRP1- and SR-BI- dependent manner. In conclusion, enhanced lipoprotein uptake due to increased activities of VEGF/NRP1 and SR-BI promotes lipid accumulation and proliferation of VHL-defective ccRCC cells.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 November 2018
Deposited On:18 Sep 2018 14:16
Last Modified:01 Dec 2018 01:12
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0022-2275
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1194/jlr.M083311
PubMed ID:30173145

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