HIF-2α-induced upregulation of CD36 promotes the development of ccRCC

Liao, Meng; Li, Yiyu; Xiao, Anhua; Lu, Qianlan; Zeng, Han; Qin, Hong; Zheng, Enze; Luo, Xiaofang; Chen, Lin; Ruan, Xiong Z.; Yang, Ping; Chen, Yaxi

doi:10.1016/j.yexcr.2022.113389

Cited by 13 publications

(6 citation statements)

References 42 publications

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“…At present, studies on CD36 have shown that the expression of CD36 in KIRC is increased [ 24 ], and the elevated level of CD36 will lead to a decrease in OS and PFS in KIRC patients [ 25 ]. Mechanistic studies on the role of CD36 in KIRC showed that CD36 was upregulated by HIF-2α, and knockdown of CD36 inhibited lipid accumulation and KIRC progression [ 26 ]. FABP5, as a fatty acid-binding protein, is mainly responsible for the conveyance of FA in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Low expression of fatty acid oxidation related gene ACADM indicates poor prognosis of renal clear cell carcinoma and is related to tumor immune infiltration

QIU,

YANG,

SUN

et al. 2024

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This research aims to identify the key fatty acid beta-oxidation (FAO) genes that are altered in kidney renal clear cell carcinoma (KIRC) and to analyze the role of these genes in KIRC. The Gene Expression Omnibus (GEO) and FAO datasets were used to identify these key genes. Wilcoxon rank sum test was used to assess the levels of acyl-CoA dehydrogenase medium chain (ACADM) between KIRC and non-cancer samples. The logistic regression and Wilcoxon rank sum test were used to explore the association between ACADM and clinical features. The diagnostic performance of ACADM for KIRC was assessed using a diagnostic receiver operating characteristic (ROC) curve. The co-expressed genes of ACADM were identified in LinkedOmics database, and their function and pathway enrichment were analyzed. The correlation between ACADM expression level and immune infiltration was analyzed by Gene Set Variation Analysis (GSVA) method. Additionally, the proliferation, migration, and invasion abilities of KIRC cells were assessed after overexpressing ACADM. Following differential analysis and intersection, we identified six hub genes, including ACADM. We found that the expression level of ACADM was decreased in KIRC tissues and had a better diagnostic effect (AUC = 0.916). Survival analysis suggested that patients with decreased ACADM expression had a worse prognosis. According to correlation analysis, a variety of clinical features were associated with the expression level of ACADM. By analyzing the infiltration level of immune cells, we found that ACADM may be related to the enrichment of immune cells. Finally, ACADM overexpression inhibited proliferation, migration, and invasion of KIRC cells. In conclusion, our findings suggest that reduced ACADM expression in KIRC patients is indicative of poor prognosis. These results imply that ACADM may be a diagnostic and prognostic marker for individuals with KIRC, offering a reference for clinicians in diagnosis and treatment.

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Section: Discussionmentioning

confidence: 99%

Low expression of fatty acid oxidation related gene ACADM indicates poor prognosis of renal clear cell carcinoma and is related to tumor immune infiltration

QIU,

YANG,

SUN

et al. 2024

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“…Four genes, CPT1A, PLIN2, CD36 and KLF6 have recently been implicated in HIF-dependent lipid accumulation in ccRCC [ 30 , 55 – 57 ]. M. Celeste Simon et al performed a preeminent study and found that PLIN2, a lipid droplet coat protein, is positively regulated by HIF2α, and promotes lipid droplet accumulation and ccRCC fitness [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

HIF-2α/LINC02609/APOL1-mediated lipid storage promotes endoplasmic reticulum homeostasis and regulates tumor progression in clear-cell renal cell carcinoma

Xiao,

Qu,

et al. 2024

J Exp Clin Cancer Res

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Background The VHL-HIF pathway and lipid droplet accumulation are the main characteristics of clear cell renal cell carcinoma (ccRCC). However, the connection between the two features is largely unknown. Methods We used transcriptional sequencing and TCGA database analysis to identify APOL1 as a novel therapeutic target for ccRCC. The oncogenic functions of APOL1 were investigated by cell proliferation, colony formation, migration and invasion assays in ccRCC cells in vitro and xenografts derived from ccRCC cells in vivo. Oil red O staining and quantification were used to detect lipid droplets. Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assays were carried out to identify HIF-2α bound to the promoter of APOL1 and lncRNA LINC02609. RNA-FISH and luciferase reporter assays were performed to determine that LncRNA LINC02609 functions as a competing endogenous RNA to regulate APOL1 expression by sponging miR-149-5p. Findings RNA-seq data revealed that HIF2α can regulate APOL1 and lncRNA LINC02609 expression. We also found that HIF-2α can bind to the promoter of APOL1 and lncRNA LINC02609 and transcriptionally regulate their expression directly. We further demonstrated that LncRNA LINC02609 functions as a competing endogenous RNA to regulate APOL1 expression by sponging miR-149-5p in ccRCC. Mechanistically, APOL1-dependent lipid storage is required for endoplasmic reticulum (ER) homeostasis and cell viability and metastasis in ccRCC. We also showed that high APOL1 expression correlated with worse clinical outcomes, and knockdown of APOL1 inhibited tumor cell lipid droplet formation, proliferation, metastasis and xenograft tumor formation abilities. Together, our studies identify that HIF2α can regulate the expression of the lipid metabolism related gene APOL1 by direct and indirect means, which are essential for ccRCC tumorigenesis. Interpretation Based on the experimental data, in ccRCC, the HIF-2α/LINC02609/APOL1 axis can regulate the expression of APOL1, thus interfering with lipid storage, promoting endoplasmic reticulum homeostasis and regulating tumor progression in ccRCC. Together, our findings provide potential biomarkers and novel therapeutic targets for future studies in ccRCC.

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“… 44 Hif2α upregulates CD36 to promote lipid metabolism and reshape the malignant phenotype of ccRCC. 45 Eliminating Hif2α expression can inhibit tumor formation in ccRCC cells lacking VHL. 46 Under normoxic conditions, Hif2α can be hydroxylated by PHD2, followed by its binding to VHL, leading to its degradation.…”

Section: Discussionmentioning

confidence: 99%

“…VHL mutations lead to abnormal accumulation of the Hif2α protein, an oncogenic protein in ccRCC 44 . Hif2α upregulates CD36 to promote lipid metabolism and reshape the malignant phenotype of ccRCC 45 . Eliminating Hif2α expression can inhibit tumor formation in ccRCC cells lacking VHL 46 .…”

Section: Discussionmentioning

confidence: 99%

MFN2 suppresses the accumulation of lipid droplets and the progression of clear cell renal cell carcinoma

Cai,

Luo,

Wang

et al. 2024

Cancer Science

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Dissolving the lipid droplets in tissue section with alcohol during a hematoxylin and eosin (H&E) stain causes the tumor cells to appear like clear soap bubbles under a microscope, which is a key pathological feature of clear cell renal cell carcinoma (ccRCC). Mitochondrial dynamics have been reported to be closely associated with lipid metabolism and tumor development. However, the relationship between mitochondrial dynamics and lipid metabolism reprogramming in ccRCC remains to be further explored. We conducted bioinformatics analysis to identify key genes regulating mitochondrial dynamics differentially expressed between tumor and normal tissues and immunohistochemistry and Western blot to confirm. After the target was identified, we created stable ccRCC cell lines to test the impact of the target gene on mitochondrial morphology, tumorigenesis in culture cells and xenograft models, and profiles of lipid metabolism. It was found that mitofusin 2 (MFN2) was downregulated in ccRCC tissues and associated with poor prognosis in patients with ccRCC. MFN2 suppressed mitochondrial fragmentation, proliferation, migration, and invasion of ccRCC cells and growth of xenograft tumors. Furthermore, MFN2 impacted lipid metabolism and reduced the accumulation of lipid droplets in ccRCC cells. MFN2 suppressed disease progression and improved prognosis for patients with ccRCC possibly by interrupting cellular lipid metabolism and reducing accumulation of lipid droplets.

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HIF-2α-induced upregulation of CD36 promotes the development of ccRCC

Cited by 13 publications

References 42 publications

Low expression of fatty acid oxidation related gene ACADM indicates poor prognosis of renal clear cell carcinoma and is related to tumor immune infiltration

Low expression of fatty acid oxidation related gene ACADM indicates poor prognosis of renal clear cell carcinoma and is related to tumor immune infiltration

HIF-2α/LINC02609/APOL1-mediated lipid storage promotes endoplasmic reticulum homeostasis and regulates tumor progression in clear-cell renal cell carcinoma

MFN2 suppresses the accumulation of lipid droplets and the progression of clear cell renal cell carcinoma

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