Abstract
The increased requirement of fatty acids forces cancer cells to enhance uptake of fatty acids from the extracellular milieu, in addition to de novo lipogenesis. Coexpression of cluster of differentiation 36 (CD36) with fatty acid transport protein 4 (FATP4) or long-chain acyl CoA synthetase 1 (ACSL1) synergistically activated fatty acid uptake in experimental models. In this study, we investigated the immunohistochemical expression of CD36, FATP4, and ACSL1 in 180 cases of clear cell renal cell carcinoma (RCC) in comparison with 80 specimens of the normal kidney. We also examined the clinical implication of these three fatty acid transporters in RCC, which was validated by an open-access The Cancer Genome Atlas data analysis. Both CD36 and FATP4 revealed higher membranous expressions in RCC tumor cells than in normal cells. In contrast, ACSL1 expression was remarkably reduced in RCC tumor cells compared to normal cells. CD36, FATP4, and ACSL1 showed high expressions in 74 (41.1%), 85 (47.2%), and 72 (40.0%) out of 180 RCC cases, respectively. Clinically, high FATP4 in tumor cells was associated with female gender (p = 0.05), high TNM stage (p = 0.039), tumor necrosis (p = 0.009), and tumor recurrence (p = 0.037), while high ACSL1 was only related to female gender (p = 0.023). CD36 expression revealed no correlation with the clinicopathologic parameters of RCC. Increased FATP4 expression displayed an association with short recurrence-free survival (p = 0.003). In conclusion, the high FATP4 expression was clinically associated with poor prognostic factors of RCC. Overexpression of membranous FATP4 and CD36 combined with reduced cytoplasmic expression of ACSL1 might be a tumor-specific feature of RCC, contributing to the tumorigenesis and tumor progression.
Highlights
Proliferating cancer cells have high demand for energy and macromolecules, and they reprogram their cellular metabolism to consume nutrients such as glucose, glutamine, and fatty acids more efficiently [1]
Another study showed that hypoxia-inducible factor- (HIF-) 1α, which is not degraded in renal cell carcinoma (RCC), enhanced the expression of a very low-density lipoprotein receptor, leading to uptake and accumulation of intracellular lipids [6]
This study showed that membranous expression of cluster of differentiation 36 (CD36) and fatty acid transport protein 4 (FATP4) was higher in RCC tumor tissues than in normal tissues, whereas cytoplasmic ACSL1 was reduced in RCC tumor cells
Summary
Proliferating cancer cells have high demand for energy and macromolecules, and they reprogram their cellular metabolism to consume nutrients such as glucose, glutamine, and fatty acids more efficiently [1]. The increased requirement for fatty acids forces cancer cells to upregulate de novo lipogenesis, lipolysis of intracellular lipid droplets, or uptake of fatty acids from the extracellular milieu, depending on the cell type or specific microenvironment. A recent study has reported that only 15% of RCC cases showed increased expression of fatty acid synthase, which is mandatory for lipogenesis [5]. Another study showed that hypoxia-inducible factor- (HIF-) 1α, which is not degraded in RCC, enhanced the expression of a very low-density lipoprotein receptor, leading to uptake and accumulation of intracellular lipids [6]. Some RCC tumor cells might metabolically depend on other mechanisms to provide fatty acids, such as uptake from extracellular sources, Disease Markers the significance of intracellular lipids has not been clearly elucidated
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