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Series GSE156545 Query DataSets for GSE156545
Status Public on Mar 23, 2021
Title Acquired deficiency of the peroxisomal bi-functional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in murine hepatoblastoma
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Metabolic reprogramming provides transformed cells with proliferative and/or survival advantages. However, capitalizing on this therapeutically has been only moderately successful due to the relatively small magnitude of these differences and because cancers may re-program their metabolism to evade metabolic pathway inhibition. Mice lacking the peroxisomal bi-functional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) and supplemented with the 12-carbon fatty acid lauric acid (C12) accumulate dodecanedioic acid (DDDA), a toxic C12 metabolite that causes hepatocyte necrosis and acute liver failure. In a murine model of pediatric hepatoblastoma (HB), down-regulation of Ehhadh also occurs in combination with a more general suppression of mitochondrial β- and peroxisomal ω-fatty acid oxidation (FAO) pathways. HB-bearing mice provided with C12 and/or DDDA-supplemented diets survived significantly longer than those on standard diets. The tumors also developed massive necrosis in response to short-term DDDA supplementation. Reduced Ehhadh was noted in murine hepatocellular carcinomas (HCCs) and in substantial subsets of human cancers, including HCCs. Acquired DDDA resistance was not associated with Ehhadh re-expression but was associated with 129 transcript differences ~90% of which were down-regulated in DDDA-resistant tumors and ~two-thirds of which correlated with survival in several human cancers. These transcripts often encoded components of the extracellular matrix suggesting that DDDA resistance arises from its reduced intracellular transport. Our results demonstrate the feasibility of a metabolic intervention that is non-toxic, inexpensive and likely compatible with traditional therapies. C12 and/or DDDA-containing diets could potentially be used to supplement other treatments or as alternative therapeutic choices.
 
Overall design RNA purification from five representative tumors of each group was performed using Qiagen RNAeasy columns (Qiagen, Inc., Valencia, CA) followed by DNase digestion. Sample integrity was measured using an Agilent 2100 Bioanalyzer (Agilent Technologies, Foster City, CA). All samples had RIN values of 8.5-10 prior to any further processing. Samples for sequencing were prepared using an NEB NEBNext Ultra Directional RNA Library Prep kit according to the directions provided by the vendor (New England Biolab, Beverly, MA) and sequencing was performed on a NovaSeq 600 Instrument (Illumina, Inc., San Diego, CA) by Novagene, Inc. (Sacramento, CA).
 
Contributor(s) Wang H, Prochownik EV
Citation(s) 33450224
Submission date Aug 20, 2020
Last update date Mar 23, 2021
Contact name Edward V. Prochownik
E-mail(s) prochownikev@upmc.edu, edward.prochownik@chp.edu
Phone 4126926795
Organization name Children’s Hospital of Pittsburgh
Department Section of Hematology/Oncology
Street address 4401 Penn Avenue
City pittsburgh
State/province PA
ZIP/Postal code 15201
Country USA
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (25)
GSM4733299 NFD-Liver c1
GSM4733300 NFD-Liver c12
GSM4733301 NFD-Liver c17
Relations
BioProject PRJNA658322
SRA SRP278204

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Supplementary file Size Download File type/resource
GSE156545_Expression_Browser.xlsx 33.8 Mb (ftp)(http) XLSX
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Raw data are available in SRA
Processed data are available on Series record

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