22 results on '"Daniunaite K"'
Search Results
2. Epigenetic markers to overcome limitations in prostate cancer diagnostics
- Author
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Bakavicius, A., primary, Daniunaite, K., additional, Jarmalaite, S., additional, and Jankevicius, F., additional
- Published
- 2018
- Full Text
- View/download PDF
3. DNA methylation biomarkers as noninvasive tools for prediction of treatment response in castration-resistant prostate cancer
- Author
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Daniunaite, K., primary, Bakavicius, A., additional, Lazutka, J., additional, Ulys, A., additional, Jankevicius, F., additional, and Jarmalaite, S., additional
- Published
- 2017
- Full Text
- View/download PDF
4. 10 - Urinary 3-gene methylation test for prostate cancer risk assessment
- Author
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Bakavicius, A., Daniunaite, K., Jarmalaite, S., and Jankevicius, F.
- Published
- 2019
- Full Text
- View/download PDF
5. 15 - Epigenetic markers to overcome limitations in prostate cancer diagnostics
- Author
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Bakavicius, A., Daniunaite, K., Jarmalaite, S., and Jankevicius, F.
- Published
- 2018
- Full Text
- View/download PDF
6. 37 - DNA methylation biomarkers as noninvasive tools for prediction of treatment response in castration-resistant prostate cancer
- Author
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Daniunaite, K., Bakavicius, A., Lazutka, J., Ulys, A., Jankevicius, F., and Jarmalaite, S.
- Published
- 2017
- Full Text
- View/download PDF
7. 10 - Promoter hypermethylation of tumor suppressor genes in renal cell carcinoma
- Author
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Kubiliūtė, R., Daniūnaitė, K., Žalimas, A., Jankevičius, F., and Jarmalaitė, S.
- Published
- 2017
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8. B07 - Analysis of single nucleotide polymorphisms in RNASEL, LEPR, CRY1, IL4 and CHI3L2 genes in a cohort of Lithuanian prostate cancer and benign prostatic hyperplasia patients
- Author
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Kapustina, Ž., Valaitienė, G., Daniūnaitė, K., Jarmalaitė, S., Jankevičius, F., Laurinavičius, A., and Lazutka, J.R.
- Published
- 2014
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9. Analysis of Intrinsic Breast Cancer Subtypes: The Clinical Utility of Epigenetic Biomarkers and TP53 Mutation Status in Triple-Negative Cases.
- Author
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Sadzeviciene I, Snipaitiene K, Scesnaite-Jerdiakova A, Daniunaite K, Sabaliauskaite R, Laurinaviciene A, Drobniene M, Ostapenko V, and Jarmalaite S
- Subjects
- Humans, Female, DNA Methylation, Mutation, Epigenomics, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Tumor Suppressor Protein p53 genetics, Breast Neoplasms pathology, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology
- Abstract
This study aimed at analyzing the DNA methylation pattern and TP53 mutation status of intrinsic breast cancer (BC) subtypes for improved characterization and survival prediction. DNA methylation of 17 genes was tested by methylation-specific PCR in 116 non-familial BRCA mutation-negative BC and 29 control noncancerous cases. At least one gene methylation was detected in all BC specimens and a 10-gene panel statistically significantly separated tumors from noncancerous breast tissues. Methylation of FILIP1L and MT1E was predominant in triple-negative (TN) BC, while other BC subtypes were characterized by RASSF1, PRKCB, MT1G, APC , and RUNX3 hypermethylation. TP53 mutation ( TP53-mut ) was found in 38% of sequenced samples and mainly affected TN BC cases (87%). Cox analysis revealed that TN status, age at diagnosis, and RUNX3 methylation are independent prognostic factors for overall survival (OS) in BC. The combinations of methylated biomarkers, RUNX3 with MT1E or FILIP1L , were also predictive for shorter OS, whereas methylated FILIP1L was predictive of a poor outcome in the TP53-mut subgroup. Therefore, DNA methylation patterns of specific genes significantly separate BC from noncancerous breast tissues and distinguishes TN cases from non-TN BC, whereas the combination of two-to-three epigenetic biomarkers can be an informative tool for BC outcome predictions.
- Published
- 2022
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10. Promoter Methylation of PRKCB , ADAMTS12 , and NAALAD2 Is Specific to Prostate Cancer and Predicts Biochemical Disease Recurrence.
- Author
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Daniunaite K, Bakavicius A, Zukauskaite K, Rauluseviciute I, Lazutka JR, Ulys A, Jankevicius F, and Jarmalaite S
- Subjects
- Adult, Aged, Aged, 80 and over, DNA Methylation genetics, Gene Expression Regulation, Neoplastic genetics, Humans, Intracellular Signaling Peptides and Proteins genetics, Male, Middle Aged, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Promoter Regions, Genetic genetics, Prostatic Hyperplasia pathology, Prostatic Neoplasms pathology, Transcription Factors genetics, ADAMTS Proteins genetics, Glutamate Carboxypeptidase II genetics, Prostatic Hyperplasia genetics, Prostatic Neoplasms genetics, Protein Kinase C beta genetics
- Abstract
The molecular diversity of prostate cancer (PCa) has been demonstrated by recent genome-wide studies, proposing a significant number of different molecular markers. However, only a few of them have been transferred into clinical practice so far. The present study aimed to identify and validate novel DNA methylation biomarkers for PCa diagnosis and prognosis. Microarray-based methylome data of well-characterized cancerous and noncancerous prostate tissue (NPT) pairs was used for the initial screening. Ten protein-coding genes were selected for validation in a set of 151 PCa, 51 NPT, as well as 17 benign prostatic hyperplasia samples. The Prostate Cancer Dataset (PRAD) of The Cancer Genome Atlas (TCGA) was utilized for independent validation of our findings. Methylation frequencies of ADAMTS12 , CCDC181 , FILIP1L , NAALAD2 , PRKCB, and ZMIZ1 were up to 91% in our study. PCa specific methylation of ADAMTS12 , CCDC181 , NAALAD2, and PRKCB was demonstrated by qualitative and quantitative means (all p < 0.05). In agreement with PRAD, promoter methylation of these four genes was associated with the transcript down-regulation in the Lithuanian cohort (all p < 0.05). Methylation of ADAMTS12 , NAALAD2, and PRKCB was independently predictive for biochemical disease recurrence, while NAALAD2 and PRKCB increased the prognostic power of multivariate models (all p < 0.01). The present study identified methylation of ADAMTS12 , NAALAD2, and PRKCB as novel diagnostic and prognostic PCa biomarkers that might guide treatment decisions in clinical practice.
- Published
- 2021
- Full Text
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11. Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line.
- Author
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Kubiliute R, Januskeviciene I, Urbanaviciute R, Daniunaite K, Drobniene M, Ostapenko V, Daugelavicius R, and Jarmalaite S
- Subjects
- ATP Binding Cassette Transporter, Subfamily B agonists, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Computational Biology methods, DNA Methylation, Drug Resistance, Neoplasm genetics, Epigenesis, Genetic drug effects, Epithelial-Mesenchymal Transition drug effects, Epithelial-Mesenchymal Transition genetics, Female, Gene Dosage, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Models, Biological, Transcriptome, Antineoplastic Agents pharmacology, Doxorubicin pharmacology, Drug Resistance, Neoplasm drug effects, Onium Compounds pharmacology, Organophosphorus Compounds pharmacology
- Abstract
Hyperactivation of ABC transporter ABCB1 and induction of epithelial-mesenchymal transition (EMT) are the most common mechanism of acquired cancer chemoresistance. This study describes possible mechanisms, that might contribute to upregulation of ABCB1 and synergistically boost the acquisition of doxorubicin (DOX) resistance in breast cancer MX-1 cell line. DOX resistance in MX-1 cell line was induced by a stepwise increase of drug concentration or by pretreatment of cells with an ABCB1 transporter activator tetraphenylphosphonium (TPP
+ ) followed by DOX exposure. Transcriptome analysis of derived cells was performed by human gene expression microarrays and by quantitative PCR. Genetic and epigenetic mechanisms of ABCB1 regulation were evaluated by pyrosequencing and gene copy number variation analysis. Gradual activation of canonical EMT transcription factors with later activation of ABCB1 at the transcript level was observed in DOX-only treated cells, while TPP+ exposure induced considerable activation of ABCB1 at both, mRNA and protein level. The changes in ABCB1 mRNA and protein level were related to the promoter DNA hypomethylation and the increase in gene copy number. ABCB1-active cells were highly resistant to DOX and showed morphological and molecular features of EMT. The study suggests that nongenotoxic ABCB1 inducer can possibly accelerate development of DOX resistance.- Published
- 2021
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12. Frequent DNA methylation changes in cancerous and noncancerous lung tissues from smokers with non-small cell lung cancer.
- Author
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Daniunaite K, Sestokaite A, Kubiliute R, Stuopelyte K, Kettunen E, Husgafvel-Pursiainen K, and Jarmalaite S
- Abstract
Cancer deaths account for nearly 10 million deaths worldwide each year, with lung cancer (LCa) as the leading cause of cancer-related death. Smoking is one of the major LCa risk factors, and tobacco-related carcinogens are potent mutagens and epi-mutagens. In the present study, we aimed to analyse smoking-related epigenetic changes in lung tissues from LCa cases. The study cohort consisted of paired LCa and noncancerous lung tissues (NLT) from 104 patients, 90 of whom were smokers or ex-smokers (i.e. ever smokers) at the time of diagnosis. DNA methylation status of tumour suppressor genes DAPK1, MGMT, p16, RASSF1 and RARB was screened by means of methylation-specific PCR (MSP) and further analysed quantitatively by pyrosequencing. Methylation of at least one gene was detected in 59% (61 of 104) of LCa samples and in 39% (41 of 104) of NLT. DAPK1 and RASSF1 were more frequently methylated in LCa than in NLT (P = 0.022 and P = 0.041, respectively). The levels of DNA methylation were higher in LCa than NLT at most of the analysed CpG positions. More frequent methylation of at least one gene was observed in LCa samples of ever smokers (63%, 57 of 90) as compared with never smokers (36%, 5 of 14; P = 0.019). In the ever smokers group, methylation of the genes also occurred in NLT, but was rare or absent in the samples of never smokers. Among the current smokers, RASSF1 methylation in LCa showed association with the number of cigarettes smoked per day (P = 0.017), whereas in NLT it was positively associated with the duration of smoking (P = 0.039). Similarly, p16 methylation in LCa of current smokers correlated with the larger number of cigarettes smoked per day (P = 0.047). Overall, DNA methylation changes were present in both cancerous and noncancerous tissues of LCa patients and showed associations with smoking-related parameters., (© The Author(s) 2020. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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13. Urinary DNA methylation biomarkers for prediction of prostate cancer upgrading and upstaging.
- Author
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Bakavicius A, Daniunaite K, Zukauskaite K, Barisiene M, Jarmalaite S, and Jankevicius F
- Subjects
- Biomarkers, Tumor urine, Biopsy, Glutathione S-Transferase pi genetics, Humans, Male, Neoplasm Grading, Neoplasm Staging, Prostate-Specific Antigen blood, Prostatectomy, Prostatic Neoplasms genetics, Prostatic Neoplasms surgery, Receptors, Retinoic Acid genetics, Tumor Suppressor Proteins genetics, Biomarkers, Tumor genetics, DNA Methylation, DNA, Neoplasm urine, Prostatic Neoplasms pathology
- Abstract
Background: Significant numbers of prostate cancer (PCa) patients experience tumour upstaging and upgrading in surgical specimens that cause serious problems in timely and proper selection of the treatment strategy. This study was aimed at the evaluation of a set of established epigenetic biomarkers as a noninvasive tool for more accurate PCa categorization before radical prostatectomy (RP)., Methods: Quantitative methylation-specific PCR was applied for the methylation analysis of RARB, RASSF1, and GSTP1 in 514 preoperatively collected voided or catheterized urine samples from the single-centre cohort of 1056 treatment-naïve PCa patients who underwent RP. The rates of biopsy upgrading and upstaging were analysed in the whole cohort., Results: Pathological examination of RP specimens revealed Gleason score upgrading in 27.2% and upstaging in 20.3% of the patients with a total misclassification rate of 39.0%. DNA methylation changes in at least one gene were detected in more than 80% of urine samples. Combination of the PSA test with the three-gene methylation analysis in urine was a significant predictor of pathological upstaging and upgrading (P < 0.050), however, with limited increase in overall accuracy. The PSA test or each gene alone was not informative enough., Conclusions: The urinary DNA methylation assay in combination with serum PSA may predict tumour stage or grade migration post-RP aiding in improved individual risk assessment and appropriate treatment selection. Clinical utility of these biomarkers should be proven in larger multi-centre studies.
- Published
- 2019
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14. DNA methylation of metallothionein genes is associated with the clinical features of renal cell carcinoma.
- Author
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Maleckaite R, Zalimas A, Bakavicius A, Jankevicius F, Jarmalaite S, and Daniunaite K
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Renal Cell pathology, Cell Line, Tumor, Cell Proliferation genetics, DNA Methylation genetics, Female, Gene Expression Regulation, Neoplastic genetics, Humans, Male, Middle Aged, Promoter Regions, Genetic, Carcinoma, Renal Cell genetics, Metallothionein genetics
- Abstract
Metallothioneins are low‑weight cysteine‑rich proteins responsible for metal ion homeostasis in a cell and, thus, capable of regulating cell proliferation and differentiation. Deregulation of metallothionein genes has been reported in various human tumors. However, their role in renal cell carcinoma (RCC) has been poorly investigated. In the present study, we aimed to evaluate the importance of promoter DNA methylation of selected metallothionein genes for RCC. Based on the initial analysis of kidney renal clear cell carcinoma dataset from The Cancer Genome Atlas, genes MT1E, MT1F, MT1G and MT1M were selected for qualitative methylation analysis in 30 tumors (including 10 multifocal cases), 10 pericancerous, and 30 non‑cancerous renal tissues (NRT). Methylation of MT1E and MT1M was tumor‑specific (P=0.0056 and P=0.0486, respectively) and showed moderate interfocal variation in paired tumor foci. Methylated promoter status of the two genes was associated with larger tumor size (P=0.0110 and P=0.0156, respectively). Furthermore, aberrant MT1E methylation was more frequent in tumors having necrotic zones (P=0.0449) or characterized with higher differentiation grade (P=0.0144), while MT1M was more commonly methylated in tumors with higher Fuhrman grade (P=0.0272). Only unmethylated MT1F promoter status was observed in all analyzed samples. Gene expression analysis (51 RCC and 9 NRT) revealed MT1G downregulation in tumors (P<0.0001), while lower MT1E expression levels were associated with the promoter methylation (P=0.0077). In clear cell RCC, MT1E, MT1G and MT1M expression was higher than that noted in other histological tumor subtypes (all P<0.0500). In addition, some associations were observed between metabolic syndrome‑related clinical parameters and promoter methylation or gene expression. In conclusion, the present study revealed the potential role of MT1E and MT1M promoter methylation in RCC development.
- Published
- 2019
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15. Clinical significance of miRNA host gene promoter methylation in prostate cancer.
- Author
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Daniunaite K, Dubikaityte M, Gibas P, Bakavicius A, Rimantas Lazutka J, Ulys A, Jankevicius F, and Jarmalaite S
- Subjects
- Aged, Biomarkers, Tumor genetics, Databases, Nucleic Acid, Disease-Free Survival, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic genetics, Humans, Kaplan-Meier Estimate, Lymphatic Metastasis, Male, Methylation, Middle Aged, Prognosis, Promoter Regions, Genetic genetics, Proportional Hazards Models, Prostate metabolism, Prostatectomy, Prostatic Hyperplasia genetics, MicroRNAs chemistry, MicroRNAs genetics, Prostatic Neoplasms genetics
- Abstract
Only a part of prostate cancer (PCa) patients has aggressive malignancy requiring adjuvant treatment after radical prostatectomy (RP). Biomarkers capable to predict biochemical PCa recurrence (BCR) after RP would significantly improve preoperative risk stratification and treatment decisions. MicroRNA (miRNA) deregulation has recently emerged as an important phenomenon in tumor development and progression, however, the mechanisms remain largely unstudied. In the present study, based on microarray profiling of DNA methylation in 9 pairs of PCa and noncancerous prostate tissues (NPT), host genes of miR-155-5p, miR-152-3p, miR-137, miR-31-5p, and miR-642a, -b were analyzed for promoter methylation in 129 PCa, 35 NPT, and 17 benign prostatic hyperplasia samples (BPH) and compared to the expression of mature miRNAs and their selected targets (DNMT1, KDM1A, and KDM5B). The Cancer Genome Atlas dataset was utilized for validation. Methylation of mir-155, mir-152, and mir-137 host genes was PCa-specific, and downregulation of miR-155-5p significantly correlated with promoter methylation. Higher KDM5B expression was observed in samples with methylated mir-155 or mir-137 promoters, whereas upregulation of KDM1A and DNMT1 was associated with mir-155 and mir-152 methylation status, respectively. Promoter methylation of mir-155, mir-152, and mir-31 was predictive of BCR-free survival in various Cox models and increased the prognostic value of clinicopathologic factors. In conclusion, methylated mir-155, mir-152, mir-137, and mir-31 host genes are promising diagnostic and/or prognostic biomarkers of PCa. Methylation status of particular miRNA host genes as independent variables or in combinations might assist physicians in identifying poor prognosis PCa patients preoperatively., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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16. Decreased expression of MT1E is a potential biomarker of prostate cancer progression.
- Author
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Demidenko R, Daniunaite K, Bakavicius A, Sabaliauskaite R, Skeberdyte A, Petroska D, Laurinavicius A, Jankevicius F, Lazutka JR, and Jarmalaite S
- Abstract
Differentiation of indolent and aggressive prostate carcinoma (PCa) at the time of diagnosis is currently one of the major challenges. This study aimed at identification of prognostic biomarkers to aid in predicting biochemical recurrence (BCR) of the disease. Microarray-based gene expression profiling in tissues of 8 BCR and 8 No-BCR cases revealed expression differences of 455 genes, most of which were down-regulated in BCR cases. Eleven genes were selected for validation by real-time PCR in the first PCa cohort (N = 55), while seven of them were further validated in the second, independent, PCa cohort (N = 53). Down-regulation of MT1E (p < 0.001) and GPR52 (p = 0.002) expression and up-regulated levels of EZH2 (p = 0.025) were specific biomarkers of BCR in at least one of the two PCa cohorts, but only MT1E expression retained the independent prognostic value in a multivariate analysis (p < 0.001). DNA methylation analysis (114 PCa and 24 non-cancerous tissues) showed frequent MT1E methylation in PCa (p < 0.001) and was associated (p < 0.010) with the down-regulated expression in one PCa cohort. The results of our study suggest MT1E down-regulation as a potential feature of aggressive PCa., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing interests.
- Published
- 2017
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17. Gene and miRNA expression profiles of mouse Lewis lung carcinoma LLC1 cells following single or fractionated dose irradiation.
- Author
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Stankevicius V, Kuodyte K, Schveigert D, Bulotiene D, Paulauskas T, Daniunaite K, and Suziedelis K
- Abstract
In clinical practice ionizing radiation (IR) is primarily applied to cancer treatment in the form of fractionated dose (FD) irradiation. Despite this fact, a substantially higher amount of current knowledge in the field of radiobiology comes from in vitro studies based on the cellular response to single dose (SD) irradiation. In addition, intrinsic and acquired resistance to IR remains an issue in clinical practice, leading to radiotherapy treatment failure. Numerous previous studies suggest that an improved understanding of the molecular processes involved in the radiation-induced DNA damage response to FD irradiation could improve the effectiveness of radiotherapy. Therefore, the present study examined the differential expression of genes and microRNA (miRNA) in murine Lewis lung cancer (LLC)1 cells exposed to SD or FD irradiation. The results of the present study indicated that the gene and miRNA expression profiles of LLC1 cells exposed to irradiation were dose delivery type-dependent. Data analysis also revealed that mRNAs may be regulated by miRNAs in a radiation-dependent manner, suggesting that these mRNAs and miRNAs are the potential targets in the cellular response to SD or FD irradiation. However, LLC1 tumors after FD irradiation exhibited no significant changes in the expression of selected genes and miRNAs observed in the irradiated cells in vitro , suggesting that experimental in vitro conditions, particularly the tumor microenvironment, should be considered in detail to promote the development of efficient radiotherapy approaches. Nevertheless, the present study highlights the primary signaling pathways involved in the response of murine cancer cells to irradiation. Data presented in the present study can be applied to improve the outcome and development of radiotherapy in preclinical animal model settings.
- Published
- 2017
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18. The utility of urine-circulating miRNAs for detection of prostate cancer.
- Author
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Stuopelyte K, Daniunaite K, Bakavicius A, Lazutka JR, Jankevicius F, and Jarmalaite S
- Subjects
- Adenocarcinoma chemistry, Adenocarcinoma urine, Aged, Biomarkers, Tumor analysis, Follow-Up Studies, Frozen Sections, Gene Expression Profiling, Humans, Male, MicroRNAs analysis, Middle Aged, Neoplasm Grading, Prospective Studies, Prostate-Specific Antigen blood, Prostatectomy, Prostatic Hyperplasia urine, Prostatic Neoplasms chemistry, Prostatic Neoplasms urine, ROC Curve, Reverse Transcriptase Polymerase Chain Reaction, Sensitivity and Specificity, Adenocarcinoma diagnosis, Biomarkers, Tumor urine, MicroRNAs urine, Prostatic Neoplasms diagnosis
- Abstract
Background: In this paper, the utility of urine-circulating microRNAs (miRNAs) as the potential biomarker of prostate cancer (PCa), the second most prevalent male cancer worldwide, was evaluated., Methods: Cancerous (N=56) and non-cancerous (N=16) prostate tissues were analysed on TaqMan Low Density Array, with the initial screening of 754 miRNAs in a subset of the samples. The abundance of selected miRNAs was analysed in urine specimens from two independent cohorts of patients with PCa (N=215 overall), benign prostatic hyperplasia (BPH; N=23), and asymptomatic controls (ASC; N=62) by means of quantitative reverse transcription PCR., Results: Over 100 miRNAs were found deregulated in PCa as compared with non-cancerous prostate tissue. After thorough validation, four miRNAs were selected for the analysis in urine specimens. The abundance of miR-148a and miR-375 in urine was identified as specific biomarkers of PCa in both cohorts. Combined analysis of urine-circulating miR-148a and miR-375 was highly sensitive and specific for PCa in both cohorts (AUC=0.79 and 0.84) and strongly improved the diagnostic power of the PSA test (AUC=0.85, cohort PCa1), including the grey diagnostic zone (AUC=0.90)., Conclusions: Quantitative measurement of urine-circulating miR-148a and miR-375 can serve as the non-invasive tool for sensitive and specific detection of PCa.
- Published
- 2016
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19. Epigenetic regulation of human adipose-derived stem cells differentiation.
- Author
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Daniunaite K, Serenaite I, Misgirdaite R, Gordevicius J, Unguryte A, Fleury-Cappellesso S, Bernotiene E, and Jarmalaite S
- Subjects
- 5-Methylcytosine metabolism, Adult Stem Cells metabolism, Cell Line, Cell Lineage, Cytosine analogs & derivatives, Cytosine metabolism, Gene Expression Profiling methods, Gene Expression Regulation, Developmental, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Mixed Function Oxygenases genetics, Mixed Function Oxygenases metabolism, Nanog Homeobox Protein, Octamer Transcription Factor-3 genetics, Octamer Transcription Factor-3 metabolism, Oligonucleotide Array Sequence Analysis, Osteoblasts metabolism, Phenotype, Pluripotent Stem Cells metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Real-Time Polymerase Chain Reaction, SOXB1 Transcription Factors genetics, SOXB1 Transcription Factors metabolism, Adipose Tissue cytology, Adult Stem Cells physiology, Cell Differentiation genetics, Epigenesis, Genetic, Osteoblasts physiology, Osteogenesis genetics, Pluripotent Stem Cells physiology
- Abstract
Adult stem cells have more restricted differentiation potential than embryonic stem cells (ESCs), but upon appropriate stimulation can differentiate into cells of different germ layers. Epigenetic factors, including DNA modifications, take a significant part in regulation of pluripotency and differentiation of ESCs. Less is known about the epigenetic regulation of these processes in adult stem cells. Gene expression profile and location of DNA modifications in adipose-derived stem cells (ADSCs) and their osteogenically differentiated lineages were analyzed using Agilent microarrays. Methylation-specific PCR and restriction-based quantitative PCR were applied for 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) detection in selected loci. The level of DNA modifications in the POU5F1 locus was quantified with deep sequencing. Expression levels of selected genes were assayed by real-time PCR. ADSCs differentiation into osteogenic lineages involved marked changes in both 5mC and 5hmC profiles, but 5hmC changes were more abundant. 5mC losses and 5hmC gains were the main events observed during ADSCs differentiation, and were accompanied by increased expression of TET1 (P = 0.009). In ADSCs, POU5F1 was better expressed than NANOG or SOX2 (P ≤ 0.001). Both 5mC and 5hmC marks were present in the POU5F1 locus, but only hydroxymethylation of specific cytosine showed significant effect on the gene expression. In summary, the data of our study suggest significant involvement of changes in 5hmC profile during the differentiation of human adult stem cells.
- Published
- 2015
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20. Frequent down-regulation of ABC transporter genes in prostate cancer.
- Author
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Demidenko R, Razanauskas D, Daniunaite K, Lazutka JR, Jankevicius F, and Jarmalaite S
- Subjects
- ATP Binding Cassette Transporter, Subfamily B genetics, Cluster Analysis, CpG Islands, DNA Methylation, Down-Regulation, Gene Expression Profiling, Humans, Male, Multigene Family, Neoplasm Grading, Neoplasm Staging, Prostatic Neoplasms pathology, Transcription Initiation Site, ATP-Binding Cassette Transporters genetics, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms genetics
- Abstract
Background: ATP-binding cassette (ABC) transporters are transmembrane proteins responsible for the efflux of a wide variety of substrates, including steroid metabolites, through the cellular membranes. For better characterization of the role of ABC transporters in prostate cancer (PCa) development, the profile of ABC transporter gene expression was analyzed in PCa and noncancerous prostate tissues (NPT)., Methods: TaqMan Low Density Array (TLDA) human ABC transporter plates were used for the gene expression profiling in 10 PCa and 6 NPT specimens. ABCB1 transcript level was evaluated in a larger set of PCa cases (N = 78) and NPT (N = 15) by real-time PCR, the same PCa cases were assessed for the gene promoter hypermethylation by methylation-specific PCR., Results: Expression of eight ABC transporter genes (ABCA8, ABCB1, ABCC6, ABCC9, ABCC10, ABCD2, ABCG2, and ABCG4) was significantly down-regulated in PCa as compared to NPT, and only two genes (ABCC4 and ABCG1) were up-regulated. Down-regulation of ABC transporter genes was prevalent in the TMPRSS2-ERG-negative cases. A detailed analysis of ABCB1 expression confirmed TLDA results: a reduced level of the transcript was identified in PCa in comparison to NPT (p = 0.048). Moreover, the TMPRSS2-ERG-negative PCa cases showed significantly lower expression of ABCB1 in comparison to NPT (p = 0.003) or the fusion-positive tumors (p = 0.002). Promoter methylation of ABCB1 predominantly occurred in PCa and was rarely detected in NPT (p < 0.001)., Conclusions: The study suggests frequent down-regulation of the ABC transporter genes in PCa, especially in the TMPRSS2-ERG-negative tumors.
- Published
- 2015
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21. Heterogeneity of DNA methylation in multifocal prostate cancer.
- Author
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Serenaite I, Daniunaite K, Jankevicius F, Laurinavicius A, Petroska D, Lazutka JR, and Jarmalaite S
- Subjects
- Aged, DNA, Neoplasm metabolism, Epigenomics, Estrogen Receptor alpha genetics, Glutathione S-Transferase pi genetics, Humans, Male, Middle Aged, Prostate metabolism, Prostatic Hyperplasia genetics, Prostatic Hyperplasia metabolism, Prostatic Neoplasms metabolism, Receptors, Retinoic Acid genetics, Tumor Suppressor Proteins genetics, DNA Methylation genetics, DNA, Neoplasm genetics, Genetic Heterogeneity, Promoter Regions, Genetic genetics, Prostatic Neoplasms genetics
- Abstract
Most prostate cancer (PCa) cases are multifocal, and separate foci display histological and molecular heterogeneity. DNA hypermethylation is a frequent alteration in PCa, but interfocal heterogeneity of these changes has not been extensively investigated. Ten pairs of foci from multifocal PCa and 15 benign prostatic hyperplasia (BPH) samples were obtained from prostatectomy specimens, resulting altogether in 35 samples. Methylation-specific PCR (MSP) was used to evaluate methylation status of nine tumor suppressor genes (TSGs), and a set of selected TSGs was quantitatively analyzed for methylation intensity by pyrosequencing. Promoter sequences of the RASSF1 and ESR1 genes were methylated in all paired PCa foci, and frequent (≥75 %) DNA methylation was detected in RARB, GSTP1, and ABCB1 genes. MSP revealed different methylation status of at least one gene in separate foci in 8 out of 10 multifocal tumors. The mean methylation level of ESR1, GSTP1, RASSF1, and RARB differed between the paired foci of all PCa cases. The intensity of DNA methylation in these TSGs was significantly higher in PCa cases than in BPH (p < 0.001). Hierarchical cluster analysis revealed a divergent methylation profile of paired PCa foci, while the foci from separate cases with biochemical recurrence showed similar methylation profile and the highest mean levels of DNA methylation. Our findings suggest that PCa tissue is heterogeneous, as between paired foci differences in DNA methylation status were found. Common epigenetic profile of recurrent tumors can be inferred from our data.
- Published
- 2015
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22. Prognostic value of RASSF1 promoter methylation in prostate cancer.
- Author
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Daniunaite K, Jarmalaite S, Kalinauskaite N, Petroska D, Laurinavicius A, Lazutka JR, and Jankevicius F
- Subjects
- Humans, Male, Prognosis, DNA Methylation, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Purpose: Patients with prostate cancer who have biochemical recurrence after curative therapy are at higher risk for distant metastasis and cancer specific death. Assessment of aberrant DNA methylation in urine might complement currently used clinical prognostic factors and serve as a noninvasive tool for early prediction of biochemical recurrence after radical prostatectomy., Materials and Methods: Promoter methylation of 7 genes was evaluated by methylation sensitive polymerase chain reaction in 149 prostate cancer tissues, 37 noncancerous prostate tissues and 17 benign prostatic hyperplasia samples. Quantitative polymerase chain reaction was used for DNA methylation analysis of the urine of 253 patients with prostate cancer and 32 with benign prostatic hyperplasia., Results: In prostate cancer tissue the most frequently methylated genes were RASSF1, GSTP1 and RARB, which combined were positively identified in 85% of cases. These genes were also methylated in the urine of 60% of patients with prostate cancer. RASSF1 was methylated in 45% of prostate cancer urine samples with methylation intensity significantly higher in prostate cancer than in benign prostatic hyperplasia cases (p = 0.018). In a univariate model RASSF1 methylation and the total number of methylated genes in prostate cancer tissue were predictive of time to biochemical recurrence (p = 0.019 and 0.043, respectively). On multivariate analysis RASSF1 methylation together with pathological stage was the most significant predictor of biochemical recurrence in patients with Gleason score 6 tumors when analyzed in tissue and urine (p ≤0.001)., Conclusions: Hypermethylation of RASSF1 in cancerous tissue and urine from patients with prostate cancer correlated with biochemical recurrence after radical prostatectomy. The prognostic potential of this biomarker deserves further investigation., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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