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The Hypoxic Microenvironment Induces Stearoyl-CoA Desaturase-1 Overexpression and Lipidomic Profile Changes in Clear Cell Renal Cell Carcinoma.

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). It is characterized by a high cell proliferation and the ability to store lipids. Previous studies have demonstrated the overexpression of enzymes associated with lipid metabolism, including stearoyl-CoA desaturase-1 (SCD-1), which increases the concentration of unsaturated fatty acids in tumor cells. In this work, we studied the expression of SCD-1 in primary ccRCC tumors, as well as in cell lines, to determine its influence on the tumor lipid composition and its role in cell proliferation. The lipidomic analyses of patient tumors showed that oleic acid (18:1n-9) is one of the major fatty acids, and it is particularly abundant in the neutral lipid fraction of the tumor core. Using a ccRCC cell line model and in vitro-generated chemical hypoxia, we show that SCD-1 is highly upregulated (up to 200-fold), and this causes an increase in the cellular level of 18:1n-9, which, in turn, accumulates in the neutral lipid fraction. The pharmacological inhibition of SCD-1 blocks 18:1n-9 synthesis and compromises the proliferation. The addition of exogenous 18:1n-9 to the cells reverses the effects of SCD-1 inhibition on cell proliferation. These data reinforce the role of SCD-1 as a possible therapeutic target.

SUBMITTER: Melana JP

PROVIDER: S-EPMC8231571 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzymes in the biosynthesis of monounsaturated fatty acids from saturated fatty acids, have been gradually recognized as a potential therapeutic target for various malignancies, particularly in clear-cell renal cell carcinoma (ccRCC). However, the prognostic value of SCD1 in ccRCC is still unknown. The aim of this study is to evaluate the clinical significance of SCD1 expression in patients with ccRCC. SCD1 expression in tumor tissues obtained from 359 patients who underwent nephrectomy for ccRCC are retrospectively assessed. During a median follow-up of 63 months (range: 1-144month), 56 patients in total died before the last follow-up in this study. Survival curves were plotted with the Kaplan-Meier method and compared with the log-rank test. Meanwhile, univariate and multivariate Cox regression models were applied to evaluate the prognostic value of SCD1 expression in overall survival (OS) for ccRCC patients. Moreover, SCD1 was enrolled into a newly built nomogram with factors selected by multivariate analysis, and the calibration was built to evaluate the predictive accuracy of nomogram. High SCD1 expression occurred in 61.6% (221/359) of ccRCC patients, which was significantly associated with age (p = 0.030), TNM stage (p = 0.021), pN stage (p = 0.014), Fuhrman grade (p = 0.014) and tumor sizes (p = 0.040). In multivariate analysis, SCD1 expression was confirmed as an adverse independent prognostic factor for OS. The prognostic accuracy of TNM stage, Fuhrman grade and tumor sizes was significantly increased when SCD1 expression was added. The independent prognostic factors, pT stage, pN stage, Fuhrman grade and tumor sizes, as well as SCD1 expression were integrated to establish a predictive nomogram with high predictive accuracy. Calibration curves revealed optimal consistency between observations and prognosis. In conclusion, high SCD1 expression is an independent prognostic factor for OS in patients with ccRCC. Our data suggest that the expression of SCD1 might guide the clinical decisions for patients with ccRCC.

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The Hypoxic Microenvironment Induces Stearoyl-CoA Desaturase-1 Overexpression and Lipidomic Profile Changes in Clear Cell Renal Cell Carcinoma.

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