Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma
The accumulation of lipids is a hallmark of human clear cell renal cell carcinoma (ccRCC). Advanced ccRCC tumors frequently show increased lipid biosynthesis, but the regulation of lipid metabolism in early stage ccRCC tumors has not been studied. Here, we performed combined transcriptomics and meta...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-02-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523319304127 |
| _version_ | 1819237891129212928 |
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| author | Johannes C. van der Mijn Leiping Fu Francesca Khani Tuo Zhang Ana M. Molina Christopher E. Barbieri Qiuying Chen Steven S. Gross Lorraine J. Gudas David M. Nanus |
| author_facet | Johannes C. van der Mijn Leiping Fu Francesca Khani Tuo Zhang Ana M. Molina Christopher E. Barbieri Qiuying Chen Steven S. Gross Lorraine J. Gudas David M. Nanus |
| author_sort | Johannes C. van der Mijn |
| collection | DOAJ |
| description | The accumulation of lipids is a hallmark of human clear cell renal cell carcinoma (ccRCC). Advanced ccRCC tumors frequently show increased lipid biosynthesis, but the regulation of lipid metabolism in early stage ccRCC tumors has not been studied. Here, we performed combined transcriptomics and metabolomics on a previously characterized transgenic mouse model (TRAnsgenic Cancer of the Kidney, TRACK) of early stage ccRCC. We found that in TRACK kidneys, HIF1α activation increases transcripts of lipid receptors (Cd36, ACVRL1), lipid storage genes (Hilpda and Fabp7), and intracellular levels of essential fatty acids, including linoleic acid and linolenic acid. Feeding the TRACK mice a high-fat diet enhances lipid accumulation in the kidneys. These results show that HIF1α increases the uptake and storage of dietary lipids in this early stage ccRCC model. By then analyzing early stage human ccRCC specimens, we found similar increases in CD36 transcripts and increases in linoleic and linolenic acid relative to normal kidney samples. CD36 mRNA levels decreased, while FASN transcript levels increased with increasing ccRCC tumor stage. These results suggest that an increase in the lipid biosynthesis pathway in advanced ccRCC tumors may compensate for a decreased capacity of these advanced ccRCCs to scavenge extracellular lipids. |
| first_indexed | 2024-12-23T13:27:32Z |
| format | Article |
| id | doaj.art-26b5223318384c0ab3149631b4ea0af2 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-23T13:27:32Z |
| publishDate | 2020-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-26b5223318384c0ab3149631b4ea0af22022-12-21T17:45:16ZengElsevierTranslational Oncology1936-52332020-02-01132177185Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell CarcinomaJohannes C. van der Mijn0Leiping Fu1Francesca Khani2Tuo Zhang3Ana M. Molina4Christopher E. Barbieri5Qiuying Chen6Steven S. Gross7Lorraine J. Gudas8David M. Nanus9Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA; Department of Medical Oncology, Amsterdam University Medical Center, Amsterdam, the NetherlandsDepartment of Pharmacology, Weill Cornell Medicine, New York, NY, USADepartment of Pathology, Weill Cornell Medicine, New York, NY, USA; Department of Urology, Weill Cornell Medicine, New York, NY, USAGenomics Resources Core, Weill Cornell Medicine, New York, NY, USADivision of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USADepartment of Urology, Weill Cornell Medicine, New York, NY, USADepartment of Pharmacology, Weill Cornell Medicine, New York, NY, USADepartment of Pharmacology, Weill Cornell Medicine, New York, NY, USADepartment of Pharmacology, Weill Cornell Medicine, New York, NY, USADivision of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA; Address all correspondence to: David M. Nanus, MD, Weill Cornell Medicine, 520 E 70th Street, New York, NY 10021, USA.The accumulation of lipids is a hallmark of human clear cell renal cell carcinoma (ccRCC). Advanced ccRCC tumors frequently show increased lipid biosynthesis, but the regulation of lipid metabolism in early stage ccRCC tumors has not been studied. Here, we performed combined transcriptomics and metabolomics on a previously characterized transgenic mouse model (TRAnsgenic Cancer of the Kidney, TRACK) of early stage ccRCC. We found that in TRACK kidneys, HIF1α activation increases transcripts of lipid receptors (Cd36, ACVRL1), lipid storage genes (Hilpda and Fabp7), and intracellular levels of essential fatty acids, including linoleic acid and linolenic acid. Feeding the TRACK mice a high-fat diet enhances lipid accumulation in the kidneys. These results show that HIF1α increases the uptake and storage of dietary lipids in this early stage ccRCC model. By then analyzing early stage human ccRCC specimens, we found similar increases in CD36 transcripts and increases in linoleic and linolenic acid relative to normal kidney samples. CD36 mRNA levels decreased, while FASN transcript levels increased with increasing ccRCC tumor stage. These results suggest that an increase in the lipid biosynthesis pathway in advanced ccRCC tumors may compensate for a decreased capacity of these advanced ccRCCs to scavenge extracellular lipids.http://www.sciencedirect.com/science/article/pii/S1936523319304127 |
| spellingShingle | Johannes C. van der Mijn Leiping Fu Francesca Khani Tuo Zhang Ana M. Molina Christopher E. Barbieri Qiuying Chen Steven S. Gross Lorraine J. Gudas David M. Nanus Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma Translational Oncology |
| title | Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma |
| title_full | Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma |
| title_fullStr | Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma |
| title_full_unstemmed | Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma |
| title_short | Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma |
| title_sort | combined metabolomics and genome wide transcriptomics analyses show multiple hif1α induced changes in lipid metabolism in early stage clear cell renal cell carcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S1936523319304127 |
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