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| Status |
Public on May 22, 2020 |
| Title |
HIF-1a and HIF-2a differently regulate tumour development, metabolism and inflammation of clear cell renal cell carcinoma in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1alpha and HIF-2a transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1a as an inhibitor and HIF-2a as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Using an autochthonous ccRCC model, we show genetically that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1a and HIF-2a are required for the clear cell phenotype. Transcriptomic and proteomic analyses revealed that HIF-1alpha regulates glycolysis while HIF-2a regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2a-deficient tumours were characterised by increased antigen presentation, interferon signalling and CD8+ T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlated with altered immune microenvironment in human ccRCC. These studies reveal an oncogenic role of HIF-1alpha in ccRCC initiation and suggest that alterations in the balance of HIF-1alpha and HIF-2a activities can affect different aspects of ccRCC biology and disease aggressiveness.
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| Overall design |
Examination of mRNA of renal or tumor biopsies
Genotype definitions:
VpR: silencing of the genes Vhl, Trp53 and Rb1
VpRH1: silencing of the genes Vhl, Trp53, Rb1 and HIF1A
VpRH: silencing of the genes Vhl, Trp53, Rb1 and HIF2A
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| Contributor(s) |
Höfflin R, Harlander S, Schäfer S, Metzger P, Kuo F, Schönenberger D, Adlesic M, Peighambari A, Seidel P, Chen C, Consenza-Contreras M, Jud A, Lahrmann B, Grabe N, Heide D, Uhl F, Chan TA, Duyster J, Zeiser R, Schell C, Heikenwalder M, Schilling O, Hakimi AA, Boerries M, Frew IJ |
| Citation(s) |
32807776 |
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| Submission date |
May 21, 2020 |
| Last update date |
Aug 21, 2020 |
| Contact name |
Patrick Metzger |
| Organization name |
University Hospital Freiburg
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| Department |
Institute for Medical Bioinformatics and Systems Medicine
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| Street address |
Breisacher Str. 153
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| City |
Freiburg |
| ZIP/Postal code |
79110 |
| Country |
Germany |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (39)
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| Relations |
| BioProject |
PRJNA634318 |
| SRA |
SRP262602 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE150983_RAW.tar |
10.0 Mb |
(http)(custom) |
TAR (of TAB) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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