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Series GSE57002 Query DataSets for GSE57002
Status Public on Apr 30, 2014
Title Mutant IDH inhibits HNF4a to disrupt hepatocyte differentiation and promote cholangiocarcinoma.
Organism Mus musculus
Experiment type Expression profiling by array
Summary Gene expression of mouse hepatoblasts (HBs) expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays that were processed at the Dana-Farber Cancer Institute core facility (http://macf-web.dfci.harvard.edu/) using their standard protocol.
Mutations in Isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly primary liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alphaketoglutarate (aKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple aKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks primary liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF4a, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models (GEMMs) expressing mutant IDH in the adult liver show aberrant response to hepatic injury, characterized by HNF4a silencing, impaired hepatocyte differentiation and markedly elevated levels of cell proliferation. Moreover, mutant IDH and activated Kras, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis and present a novel GEMM of IDH-driven malignancy.
 
Overall design Gene expression of HBs expressing IDH1 WT, IDH1 R132C, IDH2 WT, IDH2 R172K and empty vector controls under a doxycycline-inducible system (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays.
 
Contributor(s) Saha SK, Parachoniak CA, Bardeesy N, Ross KN
Citation(s) 25043045
Submission date Apr 23, 2014
Last update date May 04, 2018
Contact name Kenneth N Ross
E-mail(s) Kenneth.Ross@dfci.harvard.edu
Organization name Dana-Farber Cancer Institute
Department Pediatric Oncology
Street address 450 Brookline Ave., Rm M640
City Boston
State/province MA
ZIP/Postal code 02115
Country USA
 
Platforms (1)
GPL8321 [Mouse430A_2] Affymetrix Mouse Genome 430A 2.0 Array
Samples (14)
GSM1372810 IHCC_Vector_Collagen_Rep1
GSM1372811 IHCC_Vector_Collagen_Rep2
GSM1372812 IHCC_IDH1_WT_Collagen_Rep1
Relations
BioProject PRJNA245196

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE57002_RAW.tar 29.0 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file
Processed data included within Sample table

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