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To detect the expression of sphingosine kinase 1 (SPHK1) in clear cell renal cell carcinoma (ccRCC) and explore its biological role in the occurrence and development of ccRCC through regulation of fatty acid metabolism. Using the Cancer Genome Atlas database, SPHK1 expression and its clinical significance were detected in clear cell renal cell carcinoma. Immunohistochemistry was performed to detect SPHK1 expression in RCC samples in our hospital. The connection between the SPHK1 levels and clinicopathological features of patients was assessed. Nile Red was used to detect fatty acids in cells. Cell Counting Kit-8 and 5-ethynyl-2′-deoxyuridine assays were performed to determine the effect of SPHK1 on renal cell viability and proliferation, respectively. Additionally, the effects of SPHK1 on the proliferation and metastasis of ccRCC were studied using wound healing and Transwell assays. Fatty acids were added exogenously in recovery experiments and western blotting was performed to determine the effect of SPHK1 on fatty acid metabolism in ccRCC. Finally, the effects of SPHK1 on tumor growth were investigated in a xenograft model. Bioinformatics analysis revealed that SPHK1 expression was upregulated in kidney RCC. OverSPHK1 expression was associated with poor prognosis for ccRCC patients. High SPHK1 expression was detected in human ccRCC. SPHK1 expression was related to clinicopathological features, such as tumor size and Furman grade. Additionally, cell proliferation, migration, and invasion were inhibited in ccRCC cells with low SPHK1 expression. In rescue experiments, proliferation, migration, and invasion were restored. In vivo, reduced SPHK1 levels correlated with lower expression of fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl CoA carboxylase, and slowed tumor growth. SPHK1 is abnormally overexpressed in human ccRCC. Patients with ccRCC may benefit from treatments that target SPHK1, which may also serve as a prognostic indicator. [ABSTRACT FROM AUTHOR]

• MFN2 was downregulated in human kidney renal clear cell carcinoma (KIRC). • Lower expression of MFN2 was associated with an inferior tumor prognosis in KIRC. • MFN2 expression was significantly associated with immune cell infiltration in KIRC. • MFN2 overexpression inhibited the KIRC cell proliferation and migration abilities. Treatment of advanced kidney renal clear cell carcinoma (KIRC) remains challenging in clinic. The functional role and prognostic significance of MFN2 in KIRC are still unclear. In this study, we first performed a bioinformatic analysis to determine the expression level and prognostic value of MFN2 in KIRC using The Cancer Genome Atlas (TCGA) dataset, and then validated the MFN2 mRNA expression in our cohort of clinical tissue samples and cell lines of KIRC via RT-qPCR. Cox regression model was used to identify the independent prognostic factors. A nomogram was constructed to predict the prognosis of KIRC patients. Gene set enrichment analysis (GSEA) was performed to predict the involved functional pathways of MFN2 co-expressed genes. The association between MFN2 expression level and immune cell infiltration was assessed using the TIMER and the TIDISB databases. In addition, cell proliferation and migration abilities of two KIRC cell lines with MFN2 overexpression were evaluated by MTS and wound healing assays, respectively. Downregulation of MFN2 was observed in KIRC tissues and cell lines compared to the normal controls. Kaplan-Meier curve analysis indicated an inferior survival outcomes in KIRC patients with lower MFN2 expression, uncovering the tumor-suppressive role of MFN2 in KIRC. Cox regression results showed that higher MFN2 expression was one of the independent protective factors in KIRC. Besides, function predictive analysis revealed that MFN2 co-expressed genes were enriched in the biological processes of energy metabolism and autophagy. Moreover, MFN2 expression was observed to be significantly associated with immune cell infiltration and a variety of markers of tumor infiltrating immune cells (TIICs) including multiple immune checkpoints in KIRC tissues. Finally, MFN2 overexpression significantly inhibited cell proliferation and migration abilities of two KIRC cell lines examined. Generally, our data suggested that MFN2 may serve as a potential prognostic biomarker and therapeutic target in KIRC. [ABSTRACT FROM AUTHOR]