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Published on: July 18, 2019
Cellular hierarchy framework based on single-cell and bulk RNA sequencing reveals fatty acid metabolic biomarker
Ning Wang1, Ziyu Xu1, Lina Zhang1,2
1Department of Nephrology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China.
Background:
Fatty acid metabolism (FAM) reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Nevertheless, the effect of FAM reprogramming on the heterogeneity and prognosis of ccRCC individuals remains insufficiently understood.
Methods:
We utilized single-cell sequencing and spatial transcriptomics to investigate the heterogeneity of FAM in ccRCC comprehensively. Functional enrichment algorithms, including AUCell, UCell, singscore, ssGSEA, and AddModuleScore, along with hdWGCNA analysis, were used to identify hub genes influencing high FAM of ccRCC. Machine learning methods were then applied to pinpoint the optimal feature gene. The function of the selected genes in FAM was validated through clinical samples and cellular functional experiments.
Results:
The results revealed significant upregulation of FAM in malignant epithelial cells. Through five distinct enrichment scoring methods and hdWGCNA analysis, we redefined a gene set related to increased FAM at the single-cell level. By the integration of this gene set with bulk transcriptomic data and the application of machine-learning algorithms, we found four candidate genes-MYDGF, ZNHIT1, HMGN3, and ARL6IP4-that were linked to ccRCC progression. Bulk RNA sequencing validated their increased expression in ccRCC individuals, underscoring their diagnostic and prognostic potential. Single-cell analysis further revealed that these genes were primarily upregulated in malignant epithelial cells, emphasizing their cell-specific roles in ccRCC. It was verified that MYDGF could promote cell proliferation, migration and invasion while inhibiting cell apoptosis. Functional experiments further confirmed that MYDGF is a key FAM-related biomarker that enhances lipid deposition by suppressing fatty acid oxidation, thereby accelerating tumor progression.
Conclusions:
MYDGF was identified as a FAM-related oncogenic biomarker that promotes ccRCC progression by inhibiting fatty acid oxidation. Our findings elucidated the cellular hierarchy of ccRCC from the perspective of FAM reprogramming and may offer new insights and therapeutic targets for future ccRCC treatments.
Insights
Fatty acid metabolism reprogramming drives clear cell renal cell carcinoma (ccRCC) progression. MYDGF, a key gene, promotes ccRCC by inhibiting fatty acid oxidation, offering potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Fatty acid metabolism (FAM) reprogramming is a hallmark of clear cell renal cell carcinoma (ccRCC).
- The specific impact of FAM reprogramming on ccRCC heterogeneity and patient prognosis remains unclear.
Purpose of the Study:
- To comprehensively investigate FAM heterogeneity in ccRCC using single-cell and spatial transcriptomics.
- To identify key genes associated with altered FAM and ccRCC progression.
Main Methods:
- Utilized single-cell sequencing and spatial transcriptomics.
- Applied functional enrichment algorithms (AUCell, UCell, singscore, ssGSEA, AddModuleScore) and hdWGCNA analysis.
- Employed machine learning for optimal feature gene selection and validated findings with clinical samples and cellular experiments.
Main Results:
- Identified significant upregulation of FAM in malignant ccRCC epithelial cells.
- Redefined FAM-related gene sets at the single-cell level and identified four candidate genes (MYDGF, ZNHIT1, HMGN3, ARL6IP4) linked to ccRCC progression.
- MYDGF was confirmed to promote proliferation, migration, and invasion while inhibiting apoptosis, and to accelerate tumor progression by suppressing fatty acid oxidation.
Conclusions:
- MYDGF is an oncogenic biomarker promoting ccRCC progression through the inhibition of fatty acid oxidation.
- Findings provide insights into ccRCC cellular hierarchy concerning FAM reprogramming.
- Identified potential new therapeutic targets for ccRCC treatment.
