TY - JOUR
T1 - Uptake of HDL-cholesterol contributes to lipid accumulation in clear cell renal cell carcinoma
AU - Kim, Jung Yeon
AU - Thompson, Bonne
AU - Han, Sungwon
AU - Lotan, Yair
AU - McDonald, Jeffrey G.
AU - Ye, Jin
N1 - Funding Information:
We would like to thank Jeff Cormier for assistance in RT-QPCR, Dr. James Brugarolas for assistance in setting up the mouse xenograft model of ccRCC, Tissue Management Shared Resource of the Simmons Cancer Center in UTSW for distribution of primary ccRCC samples and their benign controls, and UTSW live cell imaging facility for confocal microscopy and training. This work was supported by the National Institutes of Health ( GM-116106 and HL-20948 ) and the Welch Foundation ( I-1832 ).
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/12
Y1 - 2019/12
N2 - Clear cell renal cell carcinoma (ccRCC), which accounts for the majority of kidney cancer, is known to accumulate excess cholesterol. However, the mechanism and functional significance of the lipid accumulation for development of the cancer remains obscure. In this study, we analyzed 42 primary ccRCC samples, and determined that cholesterol levels of ~ 70% of the tumors were at least two-fold higher than that of benign kidney tissues. Compared to tumors without cholesterol accumulation, those containing excess cholesterol expressed higher levels of scavenger receptor BI (SR-B1), a receptor for uptake of HDL-associated cholesterol, but not genes involved in cholesterol synthesis and uptake of LDL-associated cholesterol. To further determine the roles of sterol accumulation for cancer development, we implanted ccRCC from patients into mouse kidneys using a mouse ccRCC xenograft model. Feeding mice with probucol, a compound lowing HDL-cholesterol, markedly reduced levels of cholesterol in tumors containing excess cholesterol. This treatment, however, did not affect growth of these tumors. Our study suggests that cholesterol overaccumulation in ccRCC is the consequence of increased uptake of HDL-cholesterol as a result of SR-B1 overexpression, but the lipid accumulation by itself may not play a significant role in progression of the cancer.
AB - Clear cell renal cell carcinoma (ccRCC), which accounts for the majority of kidney cancer, is known to accumulate excess cholesterol. However, the mechanism and functional significance of the lipid accumulation for development of the cancer remains obscure. In this study, we analyzed 42 primary ccRCC samples, and determined that cholesterol levels of ~ 70% of the tumors were at least two-fold higher than that of benign kidney tissues. Compared to tumors without cholesterol accumulation, those containing excess cholesterol expressed higher levels of scavenger receptor BI (SR-B1), a receptor for uptake of HDL-associated cholesterol, but not genes involved in cholesterol synthesis and uptake of LDL-associated cholesterol. To further determine the roles of sterol accumulation for cancer development, we implanted ccRCC from patients into mouse kidneys using a mouse ccRCC xenograft model. Feeding mice with probucol, a compound lowing HDL-cholesterol, markedly reduced levels of cholesterol in tumors containing excess cholesterol. This treatment, however, did not affect growth of these tumors. Our study suggests that cholesterol overaccumulation in ccRCC is the consequence of increased uptake of HDL-cholesterol as a result of SR-B1 overexpression, but the lipid accumulation by itself may not play a significant role in progression of the cancer.
KW - Cancer
KW - Cholesterol
KW - Clear cell renal cell carcinoma
KW - Kidney
KW - Lipidomics
KW - Scavenger receptors
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U2 - 10.1016/j.bbalip.2019.158525
DO - 10.1016/j.bbalip.2019.158525
M3 - Article
C2 - 31513923
AN - SCOPUS:85073684994
SN - 1388-1981
VL - 1864
JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
JF - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
IS - 12
M1 - 158525
ER -