Revealing potential lipid biomarkers in clear cell renal cell carcinoma using targeted quantitative lipidomics

Abstract

Background The high drug resistance and metabolic reprogramming of clear cell renal cell carcinoma (ccRCC) are considered responsible for poor prognosis. In-depth research at multiple levels is urgently warranted to illustrate the lipid composition, distribution, and metabolic pathways of clinical ccRCC specimens. Methods In this project, a leading-edge targeted quantitative lipidomic study was conducted using 10 pairs of cancerous and adjacent normal tissues obtained from ccRCC patients. Accurate lipid quantification was performed according to a linear equation calculated using internal standards. Qualitative and quantitative analyses of lipids were performed with multiple reaction monitoring analysis based on ultra-performance liquid chromatography (UPLC) and mass spectrometry (MS). Additionally, a multivariate statistical analysis was performed using data obtained on lipids. Results A total of 28 lipid classes were identified. Among them, the most abundant were triacylglycerol (TG), diacylglycerol (DG), phosphatidylcholine (PC), and phosphatidylethanolamine (PE). Cholesteryl ester (CE) was the lipid exhibiting the most considerable difference between normal samples and tumor samples. Lipid content, chain length, and chain unsaturation of acylcarnitine (CAR), CE, and DG were found to be significantly increased. Based on screening for variable importance in projection scores ≥1, as well as fold change limits between 0.5 and 2, 160 differentially expressed lipids were identified. CE was found to be the most significantly upregulated lipid, while TG was observed to be the most significantly downregulated lipid. Conclusion Based on the absolute quantitative analysis of lipids in ccRCC specimens, it was observed that the content and change trends varied in different lipid classes. Upregulation of CAR, CE, and DG was observed, and analysis of changes in the distribution helped clarify the causes of lipid accumulation in ccRCC and possible carcinogenic molecular mechanisms. The results and methods described herein provide a comprehensive analysis of ccRCC lipid metabolism and lay a theoretical foundation for cancer treatment.

PI3K/AKT/mTOR Dysregulation and Reprogramming Metabolic Pathways in Renal Cancer: Crosstalk with the VHL/HIF Axis

“…Moreover, among them, esterified cholesteryl presented a considerably increased level in tumoral cells compared with normal samples. Activated saturated and unsaturated FA bound by carnitine also had increased levels in tumoral renal cells versus healthy cells [226].…”

VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulation

“…It is well known that the major form of neutral lipid accumulated in ccRCC is CE but not TAG. 7 , 13 , 14 Unfortunately, most of the previous studies in ccRCC focus on fatty acid metabolism instead of cholesterol metabolism. More recently, high-density lipoprotein (HDL) has been found to be the source of cholesterol, the driving force for ccRCC growth.…”

VHL Mutation Drives Human Clear Cell Renal Cell Carcinoma Progression Through PI3K/AKT-Dependent Cholesteryl Ester Accumulation

“…It is well known that the major form of neutral lipid accumulated in ccRCC is CE but not TAG (7,13,14). Unfortunately, most of the previous studies in ccRCC focus on fatty acid metabolism instead of cholesterol metabolism.…”

“…It is well known that the major form of neutral lipid accumulated in ccRCC is CE but not TAG (7,13,14).…”