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Fedorova M.S.,RAS Engelhardt Institute of Molecular Biology | Kudryavtseva A.V.,RAS Engelhardt Institute of Molecular Biology | Lakunina V.A.,RAS Engelhardt Institute of Molecular Biology | Snezhkina A.V.,RAS Engelhardt Institute of Molecular Biology | And 12 more authors.
Molecular Biology | Year: 2015

Cell metabolic reprogramming is one of the cancer hallmarks. Glycolysis activation, along with suppression of oxidative phosphorylation and, to a lower extent, the TCA cycle, occurs in the majority of malignant tumors. A bioinformatics search for the glucose metabolism genes that are differentially expressed in colorectal cancer (CC) was performed using the data of The Cancer Genome Atlas (TCGA) Project. OGDHL for an oxoglutarate dehydrogenase complex subunit, which is involved in the TCA cycle and is indirectly responsible for the induction of apoptosis, was identified as one of the most promising candidates. A quantitative PCR analysis showed, on average, an eightfold downregulation of OGDHL in 50% (15/30) of CC samples. Based on the TCGA data, promoter hypermethylation was assumed to be a major mechanism of OGDHL inactivation. Bisulfite sequencing identified the OGDHL promoter region (+327…+767 relative to the transcription start site) that is often methylated in CC samples with downregulated ODGHL expression (80%, 8/10) and is possibly crucial for gene inactivation. Thus, frequent and significant OGDHL downregulation due to hypermethylation of a specific promoter region was demonstrated for CC. The OGDHL promoter methylation pattern was assumed to provide a marker for differential diagnosis of CIMP+ (CpG island methylator phenotype) tumors, which display dense hypermethylation of the promoter region in many genes. © 2015, Pleiades Publishing, Inc. Source


Krasnov G.S.,Russian Academy of Sciences | Dmitriev A.A.,Russian Academy of Sciences | Sadritdinova A.F.,Russian Academy of Sciences | Fedorova M.S.,Russian Academy of Sciences | And 8 more authors.
Biophysics (Russian Federation) | Year: 2015

Disruption of energy metabolism that mainly involves activation of glycolysis that occurs even at the early stages of cancer due to, for example, overexpression of hexokinases such as HK1 and HK2, for the most part represents a universal feature of malignant tumor formation. Overexpression of HK2, which is considered as a marker for a poor prognosis, is commonly believed to take place in colorectal cancer, which is the third in mortality and morbidity among the cancer cases worldwide. The RNA-sequencing data of the Cancer Genome Atlas project (the largest resource in the area of molecular oncology, which contains genomic, transcriptomic, and epigenomic data for thousands of samples of over 20 forms of cancer) were analyzed using the CrossHub software that was developed by the authors, which, on the contrary, revealed the prevalence of reduced levels of HK2 mRNA and only slight changes in the expression of the HK1 gene. The data of transcriptome analysis of colorectal cancer (283 tumor samples and 41 normal tissue samples) were in agreement with the results of the following experimental evaluation of the hexokinase gene expression using the quantitative polymerase chain reaction. Increased mRNA levels of the HK1 and HK2 genes were observed only in a minor part of the samples: 12% for HK1 and 30% for HK2. At the same time a decreased level of the HK2 gene mRNA was found in 50% of the cases. Correlation analysis showed agreement between the changes in the expression of the HK1 and HK2 genes (Spearman’s rank correlation coefficient rS = 0.43, p < 0.001), which can be explained by common deregulation mechanisms of these genes in colorectal tumors. The expression level of the HK3 gene increased significantly in 60% of the samples; it is likely that it was precisely the hexokinase 3 that contributed to the glycolysis activation in colorectal cancer. © 2015, Pleiades Publishing, Inc. Source


Krasnov G.S.,RAS Engelhardt Institute of Molecular Biology | Krasnov G.S.,Herzen Moscow Cancer Research Institute | Krasnov G.S.,Russian Academy of Medical Sciences | Dmitriev A.A.,RAS Engelhardt Institute of Molecular Biology | And 15 more authors.
Molekuliarnaia biologiia | Year: 2015

The major problem in prostate cancer treatment is the development of drug resistance and especially important, cross-resistance. The mechanisms of drug resistance, which are divided into ligand-dependent (requiring the presence of androgens in the cell) and independent (not requiring the presence of androgens) are reviewed. The mechanisms are mainly represented with mutations of the androgen receptor and expression of aberrant constitutively active splice variants, as well as up-regulation of genes involved in androgens synthesis. Source


Krasnov G.S.,RAS Engelhardt Institute of Molecular Biology | Dmitriev A.A.,RAS Engelhardt Institute of Molecular Biology | Sadritdinova A.F.,RAS Engelhardt Institute of Molecular Biology | Volchenko N.N.,Herzen Moscow Cancer Research Institute | And 11 more authors.
Molecular Biology | Year: 2015

Drug resistance and especially cross-resistance are the most important problems of therapy of prostate cancer. Drug resistance mechanisms, including ligand-dependent (requiring the presence of androgens in the cell) and independent (not requiring androgens) ones, are reviewed. The mechanisms are mainly based on mutations of the androgen receptor (AR) gene, expression of aberrant constitutively active AR splice variants, and upregulation of androgen synthesis genes. © 2015, Pleiades Publishing, Inc. Source

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