Abstract
BackgroundClear cell renal cell carcinoma (ccRCC) is essentially a metabolic disorder characterized by reprogramming of several metabolic pathways. Acyl-coenzyme A thioesterases (ACOTs) are critical enzymes involved in fatty acid metabolism; however, the roles of ACOTs in ccRCC remain unclear. This study explored ACOTs expressions and their diagnostic and prognostic values in ccRCC.MethodsThree online ccRCC datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) were utilized to measure the expressions of ACOTs in paired normal and tumor tissues. Receiver operating characteristic (ROC) curves were depicted to assess the diagnostic values of ACOTs in ccRCC. Quantitative real-time PCR and immunohistochemical analysis were performed to validate the ACOT11 expression in ccRCC cell lines and clinical samples. Survival curves and Cox regression analysis were used to evaluate the predictive values of ACOTs in clinical outcome of ccRCC patients. Functional enrichment analyses and correlation analysis were carried out to predict the potential roles of ACOT8 in tumorigenesis and progression of ccRCC.ResultsACOT1/2/8/11/13 were found to be significantly downregulated in ccRCC samples. In particular, ACOT11 was decreased in almost every matched normal-tumor pair, and had extremely high diagnostic value as shown by ROC curve analysis (AUC = 0.964). The expression of ACOT11 was further verified in ccRCC cell lines and clinical samples at mRNA and protein levels. Furthermore, clinical correlation analysis and survival analysis indicated that ACOT8 was correlated with disease progression and was an independent predictor of unfavorable outcome in ccRCC. Moreover, functional analyses suggested potential roles of ACOT8 in the regulation of oxidative phosphorylation (OXPHOS), and correlation analysis revealed an association between ACOT8 and ferroptosis-related genes in ccRCC.ConclusionOur study revealed that ACOT11 and ACOT8 are promising biomarkers for diagnosis and prognosis of ccRCC, respectively, and ACOT8 may affect ccRCC development and progression through the regulation of OXPHOS and ferroptosis. These findings may provide new strategies for precise diagnosis and personalized therapy of ccRCC.
Highlights
In the United States, kidney cancer is estimated to be the sixth most common form of cancer in men and the eighth in women in 2020, accounting for approximately 5 and 3% of all newly diagnosed cancers, respectively (Siegel et al, 2020)
Different ACOTs Are Low Expressed in clear cell renal cell carcinoma (ccRCC) Patients From The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) Databases
Two datasets downloaded from the GEO database (GSE40435 and GSE53757) that contained 101 and 72 paired ccRCC and normal kidney samples, respectively, further confirmed that ACOT1/2/8/11/13 were significantly downregulated in ccRCC (Supplementary Figures 2, 3)
Summary
In the United States, kidney cancer is estimated to be the sixth most common form of cancer in men and the eighth in women in 2020, accounting for approximately 5 and 3% of all newly diagnosed cancers, respectively (Siegel et al, 2020). The reprogramming of glucose metabolism, fatty acid metabolism, oxidative phosphorylation (OXPHOS), and amino acid metabolism such as glutamine, arginine and tryptophan have pivotal regulatory roles in development and progression of ccRCC, enabling cancer cells to thrive in the hypoxic and auxotrophic microenvironment (Wettersten et al, 2017). Among these metabolic pathways, augmented lipogenesis is one of the most significant events in ccRCC for its central roles in membrane formation, cellular signaling, and cell proliferation (Lucarelli et al, 2019). This study explored ACOTs expressions and their diagnostic and prognostic values in ccRCC
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