PMID- 25586680
OWN - NLM
STAT- MEDLINE
DCOM- 20151005
LR  - 20220812
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 46
IP  - 3
DP  - 2015 Mar
TI  - Mathematical analysis predicts imbalanced IDH1/2 expression associates with 
      2-HG-inactivating beta-oxygenation pathway in colorectal cancer.
PG  - 1181-91
LID - 10.3892/ijo.2015.2833 [doi]
AB  - Bioinformatics and computational modeling offer innovative approaches to 
      investigate cancer metabolism and predict the secondary and tertiary cellular 
      responses. Dysregulation of metabolism has also been implicated in the 
      pathophysiology of cancer. A significant proportion of patients with glioblastoma 
      and hematological malignancies harbor the mutated forms of the oxidative 
      phosphorylation (OxPhos) enzymes, isocitrate dehydrogenase (IDH) 1 or 2. The 
      mutated forms of IDH1 and IDH2 produce an oncogenic metabolite, 
      D-2-hydroxyglutarate (D2HG). A recent study of breast cancer patients showed that 
      D2HG can also be produced in the absence of mutated IDH, through an alternative 
      route involving over-activated MYC signaling. We developed a novel methodology to 
      computationally analyze gene expression in colorectal cancer (CRC), and 
      identified novel sets of genes that are associated with patient survival. The 
      study of OxPhos-related genes revealed that an imbalance between the expression 
      of IDH1 and IDH2, defined as overexpression of one isoform in relation to the 
      other, was associated with worse prognosis in CRC patients. This effect was 
      further accentuated by reduced expression of the beta-oxygenation enzyme, 
      3-D-hydroxyacyl-CoA dehydratase (HCDH) 4, which has been reported to contribute 
      to metabolism of intracellular D2HG. The present computational analysis revealed 
      a novel and potential mechanism of CRC development, through over-production of 
      D2HG when there is an imbalance between IDH1 and IDH2 expression, resulting in 
      decreased clearance of D2HG when the beta-oxidization pathway is diminished. 
      Additional validation analysis with another gene expression dataset resulted in 
      IDH1/2 imbalanced expression with a shorter DFS compared with balanced 
      expression. Altogether, these findings provide a strong rationale for studying 
      this mechanism further in order to discover novel therapeutic targets for the 
      treatment of CRC.
FAU - Koseki, Jun
AU  - Koseki J
AD  - Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka 
      University, Osaka 565-0871, Japan.
FAU - Colvin, Hugh
AU  - Colvin H
AD  - Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka 
      University, Osaka 565-0871, Japan.
FAU - Fukusumi, Takahito
AU  - Fukusumi T
AD  - Department of Frontier Science for Cancer and Chemotherapy, Graduate School of 
      Medicine, Osaka University, Osaka 565-0871, Japan.
FAU - Nishida, Naohiro
AU  - Nishida N
AD  - Department of Frontier Science for Cancer and Chemotherapy, Graduate School of 
      Medicine, Osaka University, Osaka 565-0871, Japan.
FAU - Konno, Masamitsu
AU  - Konno M
AD  - Department of Frontier Science for Cancer and Chemotherapy, Graduate School of 
      Medicine, Osaka University, Osaka 565-0871, Japan.
FAU - Kawamoto, Koichi
AU  - Kawamoto K
AD  - Department of Frontier Science for Cancer and Chemotherapy, Graduate School of 
      Medicine, Osaka University, Osaka 565-0871, Japan.
FAU - Tsunekuni, Kenta
AU  - Tsunekuni K
AD  - Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka 
      University, Osaka 565-0871, Japan.
FAU - Matsui, Hidetoshi
AU  - Matsui H
AD  - Faculty of Mathematics, Kyushu University, Fukuoka 812-8581, Japan.
FAU - Doki, Yuichiro
AU  - Doki Y
AD  - Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka 
      University, Osaka 565-0871, Japan.
FAU - Mori, Masaki
AU  - Mori M
AD  - Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka 
      University, Osaka 565-0871, Japan.
FAU - Ishii, Hideshi
AU  - Ishii H
AD  - Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka 
      University, Osaka 565-0871, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150112
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Glutarates)
RN  - 2889-31-8 (alpha-hydroxyglutarate)
RN  - EC 1.1.1.41 (IDH2 protein, human)
RN  - EC 1.1.1.41 (Isocitrate Dehydrogenase)
RN  - EC 1.1.1.42. (IDH1 protein, human)
SB  - IM
MH  - Cell Respiration/genetics
MH  - Colorectal Neoplasms/diagnosis/*genetics/*metabolism/mortality
MH  - Computational Biology/*methods
MH  - Gene Expression Profiling/statistics & numerical data
MH  - Gene Expression Regulation, Neoplastic
MH  - Genetic Association Studies/statistics & numerical data
MH  - Glutarates/*metabolism
MH  - Humans
MH  - Isocitrate Dehydrogenase/*genetics
MH  - Metabolic Networks and Pathways/genetics
MH  - Models, Theoretical
MH  - *Oxidative Phosphorylation
MH  - Prognosis
MH  - Survival Analysis
EDAT- 2015/01/15 06:00
MHDA- 2015/10/06 06:00
CRDT- 2015/01/15 06:00
PHST- 2014/09/19 00:00 [received]
PHST- 2014/11/03 00:00 [accepted]
PHST- 2015/01/15 06:00 [entrez]
PHST- 2015/01/15 06:00 [pubmed]
PHST- 2015/10/06 06:00 [medline]
AID - 10.3892/ijo.2015.2833 [doi]
PST - ppublish
SO  - Int J Oncol. 2015 Mar;46(3):1181-91. doi: 10.3892/ijo.2015.2833. Epub 2015 Jan 
      12.