ABSTRACT
The search for interacting long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs of protein-coding genes through the mechanism of competing endogenous RNAs in tumors of ovarian cancer patients was carried out. The levels of expression of 24 lncRNAs, 20 miRNAs, and 28 mRNAs of protein-coding genes involved in oncogenesis were determined by real-time PCR on a set of representative samples. Correlations between lncRNAs/miRNA and miRNA/mRNA levels in ovarian cancer samples were analyzed. We identified 8 pairs of lncRNAs/miRNA and 17 pairs of miRNA/mRNA, the expression levels of which have a negative correlation. Five triplets of potentially interacting lncRNAs/miRNA/mRNA have been identified, among which the most significant triplet is the OIP5-AS1/miR-203a-3p/ZEB1. The data obtained determine new epigenetic profiles, as well as new potential biomarkers and targets for targeted therapy of ovarian cancer patients.
Subject(s)
MicroRNAs , Ovarian Neoplasms , RNA, Long Noncoding , Humans , Female , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Gene Regulatory Networks , Ovarian Neoplasms/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Gene Expression Regulation, Neoplastic/geneticsABSTRACT
We studied the correlations between the levels of methylation of a group of 21 microRNA genes in 99 primary tumors and 29 macroscopic peritoneal metastases of ovarian cancer. Analysis of the level of methylation by quantitative methylation-specific PCR showed that co-methylation was detected for 13 pairs of microRNA genes in primary tumors and for 22 pairs in metastases. Pairs of microRNA genes that have shown significant co-methylation can be involved in common processes and pathways of gene regulation and interaction and can have common target genes. The results are highly significant and pairs of microRNA genes can be proposed as new potential markers for the diagnosis and prognosis of ovarian cancer metastasis.
Subject(s)
MicroRNAs , Ovarian Neoplasms , Carcinoma, Ovarian Epithelial/genetics , DNA Methylation/genetics , Female , Gene Expression Regulation, Neoplastic/genetics , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Ovarian Neoplasms/pathologyABSTRACT
The content of the soluble form of protein of the key point of immunity B7-H3 (sB7-H3) in the blood plasma of 75 patients with epithelial ovarian cancer before treatment was measured by ELISA. It is known that B7-H3 belongs to the immunoglobulin superfamily (B7 molecule family) and is involved in the regulation of the immune response mediated by T cells. The sB7-H3 concentration correlated with the clinical and morphological parameters of ovarian cancer. The content of sB7-H3 was higher at the later stages of the disease, in the presence of ascites, and in patients with poorly differentiated ovarian cancer. It was revealed that increased plasma content of sB7-H3 in patients with epithelial ovarian cancer is associated with unfavorable prognosis of the disease. Therefore, sB7-H3 can be used as a prognostic marker in ovarian cancer patients.
Subject(s)
B7 Antigens/blood , Carcinoma, Ovarian Epithelial/diagnosis , Ovarian Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Carcinoma, Ovarian Epithelial/blood , Carcinoma, Ovarian Epithelial/mortality , Carcinoma, Ovarian Epithelial/pathology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Middle Aged , Ovarian Neoplasms/blood , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Predictive Value of Tests , Prognosis , Survival AnalysisABSTRACT
We identified a group of miRNA genes whose methylation is associated with ovarian cancer metastasis. Based on these data, new markers and the systems of markers predicting tumor dissemination were selected. Using methylation-specific PCR and a representative set of 54 ovarian cancer samples, we identified 10 microRNA genes (MIR-124a-2, MIR-127, MIR-125b-1, MIR-129-2, MIR-137, MIR-193a, MIR-203a, MIR-34b/c, MIR-130b, and MIR-1258) whose methylation is associated with tumor metastasis. The greatest association was established for 4 genes: MIR-137, MIR-193a, MIR-34b/c, and MIR-130b (p<0.01). ROC analysis revealed 3 most optimal marker systems including 4-5 miRNA genes and characterized by high sensitivity (82-94%) and specificity (76-86%) at AUC=0.89-0.92. Methylation of any three genes from these systems is sufficient to predict metastasis with the specified accuracy. Detection of the group of hypermethylated miRNA genes with predictive value for ovarian cancer metastasis is of great importance for personalized treatment of the patients.
Subject(s)
DNA Methylation/genetics , MicroRNAs/genetics , Ovarian Neoplasms/genetics , Female , Gene Expression Regulation, Neoplastic/genetics , Humans , Polymerase Chain ReactionABSTRACT
The study was designed to determine genes of microRNAs hypermethylated in malignant ovarian tumors and to select new diagnostic and prognostic markers of the disease and effective system of markers. Using methyl-specific PCR and a representative sample of 54 ovarian cancer specimens, we determined 5 microRNA genes (MIR-34b/c, MIR-9-1, MIR-124-3, MIR-129-2, and MIR-107) hypermethylated in the majority of tumor samples in comparison with paired samples of histologically unchanged tissue (48-57% vs. 4-19%, p<0.001). Using ROC-analysis, we selected an effective system of 4 markers for diagnosis of ovarian cancer (MIR-9-1, MIR-124-3, MIR-129-2, and MIR-107) characterized by high sensitivity and specificity (up to 87-94% at AUC=0.92) relative to the conventional norm (54 paired samples of histologically unchanged tissue) and absolute norm (18 ovarian tissue samples from subjects who died from non-tumor diseases). It was also shown that methylation of MIR-129-2, MIR-9-1, and MIR-34b/c genes is significantly (p<0.01) correlated with the clinical stage or the presence of metastases. The results indicate that epigenetic modifications of the studied microRNA genes are involved in the pathogenesis and progression of ovarian cancer and attest to their diagnostic and prognostic potential.
Subject(s)
Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Ovarian Neoplasms/diagnosis , Adult , Biomarkers, Tumor/metabolism , CpG Islands , DNA Methylation , Disease Progression , Epigenesis, Genetic , Female , Humans , Lymphatic Metastasis , MicroRNAs/metabolism , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Sensitivity and SpecificityABSTRACT
We studied microRNA whose expression can be regulated by carcinogenic compounds. Bioinformatic analysis has detected microRNA potentially regulated by xenosensor receptors AhR (miR-28, miR-30c, miR-30e, miR-139, and miR-153) and CAR (miR-29c, miR-31, miR-185, miR-625, and miR-652). Published data indicate that these microRNAs are oncosuppressors, except miR-31 that can act as an oncogene. The expression of these microRNAs in malignant tumors of the endometrium was studied. The expression of the majority of the studied microRNAs, except miR-652, was 2-3-fold below the normal, which confirms their oncosuppressor function and indicates their involvement in the endometrial carcinogenesis and hence, allows considering them as potential markers of the disease.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Carcinogenesis/genetics , Endometrial Neoplasms/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Receptors, Aryl Hydrocarbon/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Aged , Basic Helix-Loop-Helix Transcription Factors/metabolism , Binding Sites , Carcinogenesis/metabolism , Carcinogenesis/pathology , Computational Biology , Constitutive Androstane Receptor , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Endometrium/metabolism , Endometrium/pathology , Female , Gene Expression Profiling , Humans , MicroRNAs/classification , MicroRNAs/metabolism , Middle Aged , Neoplasm Staging , Receptors, Aryl Hydrocarbon/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Response ElementsABSTRACT
MicroRNA and methylation are important epigenetic mechanisms in the pathogenesis of cancer. The role of a group of microRNA hypermethylated genes in the pathogenesis of ovarian cancer was studied and their diagnostic and prognostic potential was evaluated. Studies on a representative sample of 54 ovarian cancer specimens with the use of methyl-specific PCR resulted in detection of five microRNA genes (MIR-9-1, MIR-9-3, MIR-107, MIR-1258, and MIR-130b) methylated in the majority of tumor specimens in comparison with paired specimens of histologically intact tissue (37-57% vs. 4-9%, p<0.01). Methylation of three genes (MIR-9-1, MIR-9-3, and MIR-130b) was significantly (p≤0.05) associated with the parameters of ovarian cancer progress (clinical stage, differentiation degree, tumor size, and presence of metastases). These findings attest to oncosuppressive role of the studied microRNA genes (MIR-9-1, MIR-9-3, MIR-107, MIR-1258, and MIR-130b) in the pathogenesis and progress of ovarian cancer and indicated their prognostic potential.
