The CIMP-high phenotype is associated with energy metabolism alterations in colon adenocarcinoma.

Autor: Fedorova MS; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Krasnov GS; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Lukyanova EN; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Zaretsky AR; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Dmitriev AA; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Melnikova NV; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Moskalev AA; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Kharitonov SL; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Pudova EA; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Guvatova ZG; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Kobelyatskaya AA; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Ishina IA; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Slavnova EN; National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia., Lipatova AV; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Chernichenko MA; National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia., Sidorov DV; National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia., Popov AY; State Hospital №57, Moscow, Russia., Kiseleva MV; National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia., Kaprin AD; National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia., Snezhkina AV; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia., Kudryavtseva AV; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia. rhizamoeba@mail.ru.
Jazyk: angličtina
Zdroj: BMC medical genetics [BMC Med Genet] 2019 Apr 09; Vol. 20 (Suppl 1), pp. 52. Date of Electronic Publication: 2019 Apr 09.
DOI: 10.1186/s12881-019-0771-5
Abstrakt: Background: CpG island methylator phenotype (CIMP) is found in 15-20% of malignant colorectal tumors and is characterized by strong CpG hypermethylation over the genome. The molecular mechanisms of this phenomenon are not still fully understood. The development of CIMP is followed by global gene expression alterations and metabolic changes. In particular, CIMP-low colon adenocarcinoma (COAD), predominantly corresponded to consensus molecular subtype 3 (CMS3, "Metabolic") subgroup according to COAD molecular classification, is associated with elevated expression of genes participating in metabolic pathways.
Methods: We performed bioinformatics analysis of RNA-Seq data from The Cancer Genome Atlas (TCGA) project for CIMP-high and non-CIMP COAD samples with DESeq2, clusterProfiler, and topGO R packages. Obtained results were validated on a set of fourteen COAD samples with matched morphologically normal tissues using quantitative PCR (qPCR).
Results: Upregulation of multiple genes involved in glycolysis and related processes (ENO2, PFKP, HK3, PKM, ENO1, HK2, PGAM1, GAPDH, ALDOA, GPI, TPI1, and HK1) was revealed in CIMP-high tumors compared to non-CIMP ones. Most remarkably, the expression of the PKLR gene, encoding for pyruvate kinase participating in gluconeogenesis, was decreased approximately 20-fold. Up to 8-fold decrease in the expression of OGDHL gene involved in tricarboxylic acid (TCA) cycle was observed in CIMP-high tumors. Using qPCR, we confirmed the increase (4-fold) in the ENO2 expression and decrease (2-fold) in the OGDHL mRNA level on a set of COAD samples.
Conclusions: We demonstrated the association between CIMP-high status and the energy metabolism changes at the transcriptomic level in colorectal adenocarcinoma against the background of immune pathway activation. Differential methylation of at least nine CpG sites in OGDHL promoter region as well as decreased OGDHL mRNA level can potentially serve as an additional biomarker of the CIMP-high status in COAD.
Databáze: MEDLINE
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