50 results on '"Rusetska N"'
Search Results
2. Transcriptomic alterations of RRM genes in clear cell renal cell carcinoma (ccRCC) as a basis for new anticancer therapy.
- Author
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Szymanski, M.D., primary, Szarkowska, J., additional, Cwiek, P., additional, Jancewicz, I., additional, Stachowiak, M., additional, Swiatek, M., additional, Rusetska, N., additional, Zub, R., additional, Demkow, T., additional, Siedlecki, J.A., additional, Sarnowski, T.J., additional, and Sarnowska, E., additional
- Published
- 2019
- Full Text
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3. Downregulation of BRCA1 and CTCF in clear cell renal cell carcinoma
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Siedlecki, J.A., primary, Rusetska, N., additional, Szarkowska, J., additional, Szymanski, M., additional, Leszczynski, M., additional, Stachowiak, M., additional, Jancewicz, I., additional, Swiatek, M., additional, Oksinska, P., additional, Maassen, A., additional, Chmielarczyk, M., additional, Konopinski, R., additional, Chrzan, A., additional, Demkow, T., additional, Kowalik, A., additional, Sarnowska, E., additional, and Sarnowski, T.J., additional
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- 2019
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4. The mTOR kinase directly regulates FBP1 gene expression via interaction with SWI/SNF chromatin remodeling complex in clear cell renal cell carcinoma (ccRCC).
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Sarnowska, E., primary, Cwiek, P., additional, Szarkowska, J., additional, Leszczynski, M., additional, Rusetska, N., additional, Szymanski, M., additional, Jancewicz, I., additional, Stachowiak, M., additional, Kubala, S., additional, Chrzan, A., additional, Gos, A., additional, Balcerak, A., additional, Demkow, T., additional, Siedlecki, J.A., additional, and Sarnowski, T.J., additional
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- 2019
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5. The role of SWI/SNF chromatin remodelling complex ATPase subunit - BRM in TNBC
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Jancewicz, I., primary, Rusetska, N., additional, Armatowska, A., additional, Stachowiak, M., additional, Pogoda, K., additional, Niwińska, A., additional, Olszewski, W., additional, Nowecki, Z.I., additional, Sarnowski, T.J., additional, Sarnowska, E., additional, and Siedlecki, J.A., additional
- Published
- 2018
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6. HER2-positive breast cancer resistance to trastuzumab is associated with metabolic switch
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Dubianski, R., primary, Sarnowska, E., additional, Leszczynski, M., additional, Kubala, S., additional, Olszewski, W., additional, Rusetska, N., additional, Jagiello-Gruszfeld, A.I., additional, Konopinski, R., additional, Sarnowski, T.J., additional, Siedlecki, J.A., additional, and Nowecki, Z.I., additional
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- 2018
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7. PO-512 Protein markers of progression risk in patients with squamous cell vulvar carcinoma
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Kowalewska, M., primary, Fatalska, A., additional, Olędzki, J., additional, Goryca, K., additional, Bakuła-Zalewska, E., additional, Rusetska, N., additional, Kowalik, A., additional, Wroblewska, A., additional, Zalewski, K., additional, and Domański, D., additional
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- 2018
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8. Loss of SWI/SNF chromatin remodelling complex is linked to advanced urinary bladder cancer
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Szymanski, M., primary, Sarnowska, E., additional, Ornoch, A., additional, Rusetska, N., additional, Abramowicz, S., additional, Chrzan, A., additional, Ligaj, M., additional, Maassen, A., additional, Siedlecki, J., additional, and Sarnowski, T., additional
- Published
- 2017
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9. Downregulation of BRCA1 protein in clear cell renal cellular carcinoma
- Author
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Sarnowska, E., primary, Rusetska, N., additional, Szymanski, M., additional, Jancewicz, I., additional, Chmielarczyk, M., additional, Konopinski, R., additional, Leszczynski, M., additional, Chrzan, A., additional, Ligaj, M., additional, Maassen, A., additional, Sarnowski, T., additional, and Siedlecki, J., additional
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- 2017
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10. P48 - Downregulation of BRCA1 and CTCF in clear cell renal cell carcinoma
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Siedlecki, J.A., Rusetska, N., Szarkowska, J., Szymanski, M., Leszczynski, M., Stachowiak, M., Jancewicz, I., Swiatek, M., Oksinska, P., Maassen, A., Chmielarczyk, M., Konopinski, R., Chrzan, A., Demkow, T., Kowalik, A., Sarnowska, E., and Sarnowski, T.J.
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- 2019
- Full Text
- View/download PDF
11. P30 - Transcriptomic alterations of RRM genes in clear cell renal cell carcinoma (ccRCC) as a basis for new anticancer therapy.
- Author
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Szymanski, M.D., Szarkowska, J., Cwiek, P., Jancewicz, I., Stachowiak, M., Swiatek, M., Rusetska, N., Zub, R., Demkow, T., Siedlecki, J.A., Sarnowski, T.J., and Sarnowska, E.
- Published
- 2019
- Full Text
- View/download PDF
12. O17 - The mTOR kinase directly regulates FBP1 gene expression via interaction with SWI/SNF chromatin remodeling complex in clear cell renal cell carcinoma (ccRCC).
- Author
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Sarnowska, E., Cwiek, P., Szarkowska, J., Leszczynski, M., Rusetska, N., Szymanski, M., Jancewicz, I., Stachowiak, M., Kubala, S., Chrzan, A., Gos, A., Balcerak, A., Demkow, T., Siedlecki, J.A., and Sarnowski, T.J.
- Published
- 2019
- Full Text
- View/download PDF
13. 1898P - The role of SWI/SNF chromatin remodelling complex ATPase subunit - BRM in TNBC
- Author
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Jancewicz, I., Rusetska, N., Armatowska, A., Stachowiak, M., Pogoda, K., Niwińska, A., Olszewski, W., Nowecki, Z.I., Sarnowski, T.J., Sarnowska, E., and Siedlecki, J.A.
- Published
- 2018
- Full Text
- View/download PDF
14. 17P - HER2-positive breast cancer resistance to trastuzumab is associated with metabolic switch
- Author
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Dubianski, R., Sarnowska, E., Leszczynski, M., Kubala, S., Olszewski, W., Rusetska, N., Jagiello-Gruszfeld, A.I., Konopinski, R., Sarnowski, T.J., Siedlecki, J.A., and Nowecki, Z.I.
- Published
- 2018
- Full Text
- View/download PDF
15. 1720P - Downregulation of BRCA1 protein in clear cell renal cellular carcinoma
- Author
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Sarnowska, E., Rusetska, N., Szymanski, M., Jancewicz, I., Chmielarczyk, M., Konopinski, R., Leszczynski, M., Chrzan, A., Ligaj, M., Maassen, A., Sarnowski, T., and Siedlecki, J.
- Published
- 2017
- Full Text
- View/download PDF
16. 1722P - Loss of SWI/SNF chromatin remodelling complex is linked to advanced urinary bladder cancer
- Author
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Szymanski, M., Sarnowska, E., Ornoch, A., Rusetska, N., Abramowicz, S., Chrzan, A., Ligaj, M., Maassen, A., Siedlecki, J., and Sarnowski, T.
- Published
- 2017
- Full Text
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17. The Function of Chromatin Remodeling Complex SWI/SNF and VDR in Chronic Rhinosinusitis.
- Author
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Kowalik, K., Waniewska-Łęczycka, M., Sarnowska, E., Rusetska, N., Popko-Zagor, M., and .
- Published
- 2021
18. Telomere Length and TERT abnormalities in pituitary adenomas
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Boresowicz, J., Kober, P., Rusetska, N., Maksymowicz, M., Goryca, K., Kunicki, J., Bonicki, W., and Mateusz Bujko
19. Relevance of mutations in protein deubiquitinases genes and TP53 in corticotroph pituitary tumors.
- Author
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Pękul M, Szczepaniak M, Kober P, Rusetska N, Mossakowska BJ, Baluszek S, Kowalik A, Maksymowicz M, Zieliński G, Kunicki J, Witek P, and Bujko M
- Subjects
- Humans, Female, Corticotrophs metabolism, Proto-Oncogene Proteins B-raf genetics, Endopeptidases genetics, Mutation, Deubiquitinating Enzymes genetics, Deubiquitinating Enzymes metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Pituitary Neoplasms genetics, Pituitary Neoplasms metabolism, ACTH-Secreting Pituitary Adenoma metabolism, Pituitary ACTH Hypersecretion metabolism, Adenoma genetics
- Abstract
Introduction: Corticotroph pituitary neuroendocrine tumors (PitNETs) develop from ACTH-producing cells. They commonly cause Cushing's disease (CD), however, some remain clinically silent. Recurrent USP8 , USP48 , BRAF and TP53 mutations occur in corticotroph PitNETs. The aim of our study was to determine frequency and relevance of these mutations in a possibly large series of corticotroph PitNETs., Methods: Study included 147 patients (100 CD and 47 silent tumors) that were screened for hot-spot mutations in USP8 , USP48 and BRAF with Sanger sequencing, while 128 of these patients were screened for TP53 mutations with next generation sequencing and immunohistochemistry., Results: USP8 mutations were found in 41% CD and 8,5% silent tumors, while USP48 mutations were found in 6% CD patients only. Both were more prevalent in women. They were related to higher rate of biochemical remission, non-invasive tumor growth, its smaller size and densely granulated histology, suggesting that these mutation may be favorable clinical features. Multivariate survival analyses did not confirm possible prognostic value of mutation in protein deubiquitinases. No BRAF mutations were found. Four TP53 mutations were identified (2 in CD, 2 in silent tumors) in tumors with size >10mm including 3 invasive ones. They were found in Crooke's cell and sparsely granulated tumors. Tumors with missense TP53 mutations had higher TP53 immunoreactivity score than wild-type tumors. Tumor with frameshift TP53 variant had low protein expression. TP53 mutation was a poor prognostic factor in CD according to uni- and multivariate survival analyses in spite of low mutations frequency., Conclusions: We confirmed high prevalence of USP8 mutations and low incidence of USP48 and TP53 mutations. Changes in protein deubiquitinases genes appear to be favorable prognostic factors in CD. TP53 mutations are rare, occur in both functioning and silent tumors and are related to poor clinical outcome in CD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pękul, Szczepaniak, Kober, Rusetska, Mossakowska, Baluszek, Kowalik, Maksymowicz, Zieliński, Kunicki, Witek and Bujko.)
- Published
- 2024
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20. Epigenetic Downregulation of Hsa-miR-193b-3p Increases Cyclin D1 Expression Level and Cell Proliferation in Human Meningiomas.
- Author
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Kober P, Mossakowska BJ, Rusetska N, Baluszek S, Grecka E, Konopiński R, Matyja E, Oziębło A, Mandat T, and Bujko M
- Subjects
- Adult, Humans, Cell Proliferation genetics, Cyclin D1 genetics, Down-Regulation genetics, Epigenesis, Genetic, Meningeal Neoplasms genetics, Meningioma genetics, MicroRNAs genetics
- Abstract
Meningiomas are common intracranial tumors in adults. Abnormal microRNA (miRNA) expression plays a role in their pathogenesis. Change in miRNA expression level can be caused by impaired epigenetic regulation of miRNA-encoding genes. We found the genomic region covering the MIR193B gene to be DNA hypermethylated in meningiomas based on analysis of genome-wide methylation (HumanMethylation450K Illumina arrays). Hypermethylation of MIR193B was also confirmed via bisulfite pyrosequencing. Both hsa-miR-193b-3p and hsa-miR-193b-5p are downregulated in meningiomas. Lower expression of hsa-miR-193b-3p and higher MIR193B methylation was observed in World Health Organization (WHO) grade (G) II/III tumors as compared to GI meningiomas. CCND1 mRNA was identified as a target of hsa-miR-193b-3p as further validated using luciferase reporter assay in IOMM-Lee meningioma cells. IOMM-Lee cells transfected with hsa-miR-193b-3p mimic showed a decreased cyclin D1 level and lower cell viability and proliferation, confirming the suppressive nature of this miRNA. Cyclin D1 protein expression (immunoreactivity) was higher in atypical than in benign meningiomas, accordingly to observations of lower hsa-miR-193b-3p levels in GII tumors. The commonly observed hypermethylation of MIR193B in meningiomas apparently contributes to the downregulation of hsa-miR-193b-3p. Since hsa-miR-193b-3p regulates proliferation of meningioma cells through negative regulation of cyclin D1 expression, it seems to be an important tumor suppressor in meningiomas.
- Published
- 2023
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21. DNA methylation, combined with RNA sequencing, provide novel insight into molecular classification of chordomas and their microenvironment.
- Author
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Baluszek S, Kober P, Rusetska N, Wągrodzki M, Mandat T, Kunicki J, and Bujko M
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- Humans, CpG Islands, Gene Expression Profiling, Sequence Analysis, RNA, Tumor Microenvironment, DNA Methylation, Chordoma genetics
- Abstract
Chordomas are rare tumors of notochord remnants, occurring mainly in the sacrum and skull base. Despite of their unusually slow growth, chordomas are highly invasive and the involvement of adjacent critical structures causes treatment challenges. Due to the low incidence, the molecular pathogenesis of this entity remains largely unknown. This study aimed to investigate DNA methylation abnormalities and their impact on gene expression profiles in skull base chordomas. 32 tumor and 4 normal nucleus pulposus samples were subjected to DNA methylation and gene expression profiling with methylation microarrays and RNA sequencing. Genome-wide DNA methylation analysis revealed two distinct clusters for chordoma (termed subtypes C and I) with different patterns of aberrant DNA methylation. C Chordomas were characterized by general hypomethylation with hypermethylation of CpG islands, while I chordomas were generally hypermethylated. These differences were reflected by distinct distribution of differentially methylated probes (DMPs). Differentially methylated regions (DMRs) were identified, indicating aberrant methylation in known tumor-related genes in booth chordoma subtypes and regions encoding small RNAs in subtype C chordomas. Correlation between methylation and expression was observed in a minority of genes. Upregulation of TBXT in chordomas appeared to be related to lower methylation of tumor-specific DMR in gene promoter. Gene expression-based clusters of tumor samples did not overlap with DNA methylation-based subtypes. Nevertheless, they differ in transcriptomic profile that shows immune infiltration in I chordomas and up-regulation of cell cycle in C chordomas. Immune enrichment in chordomas I was confirmed with 3 independent deconvolution methods and immunohistochemistry. Copy number analysis showed higher chromosomal instability in C chordomas. Nine out of eight had deletion of CDKN2A/B loci and downregulation of genes encoded in related chromosomal band. No significant difference in patients' survival was observed between tumor subtypes, however, shorter survival was observed in patients with higher number of copy number alterations., (© 2023. The Author(s).)
- Published
- 2023
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22. The expression of glucocorticoid and mineralocorticoid receptors in pituitary tumors causing Cushing's disease and silent corticotroph tumors.
- Author
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Kober P, Rusetska N, Mossakowska BJ, Maksymowicz M, Pękul M, Zieliński G, Styk A, Kunicki J, Działach Ł, Witek P, and Bujko M
- Subjects
- Humans, Glucocorticoids metabolism, Corticotrophs metabolism, Hydrocortisone, Receptors, Mineralocorticoid genetics, Hypothalamo-Hypophyseal System metabolism, Adrenocorticotropic Hormone metabolism, Pituitary-Adrenal System metabolism, Pituitary Neoplasms complications, Pituitary Neoplasms genetics, Pituitary Neoplasms metabolism, Pituitary ACTH Hypersecretion surgery, Adenoma complications, Adenoma genetics, Adenoma metabolism
- Abstract
Objective: Pituitary neuroendocrine corticotroph tumors commonly cause Cushing's disease (CD) that results from increased adrenocorticotropic hormone (ACTH) secretion by the pituitary tumor and consequent increase of cortisol levels in blood. However, in some patients, corticotroph tumors remain clinically non-functioning. Cortisol secretion is regulated by the hypothalamic-pituitary-adrenal axis and includes a negative feedback between cortisol and ACTH secretion. Glucocorticoids reduce ACTH level both by hypothalamic regulation and acting on corticotrophs via glucocorticoid (GR) and mineralocorticoid (MR) receptors. The aim of the study was to determine the role of GR and MR expression at mRNA and protein levels in both functioning and silent corticotroph tumors., Methods: Ninety-five patients were enrolled, including 70 with CD and 25 with silent corticotroph tumors. Gene expression levels of NR3C1 and NR3C2 coding for GR and MR, respectively, were determined with qRT-PCR in the two tumor types. GR and MR protein abundance was assessed with immunohistochemistry., Results: Both GR and MR were expressed in corticotroph tumors. Correlation between NR3C1 and NR3C2 expression levels was observed. NR3C1 expression was higher in silent than in functioning tumors. In CD patients NR3C1 and NR3C2 levels were negatively correlated with morning plasma ACTH levels and tumor size. Higher NR3C2 was confirmed in patients with remission after surgery and in densely granulated tumors. Expression of both genes and GR protein was higher in USP8 -mutated tumors. Similar relationship between USP8 mutations and expression levels were observed in analysis of silent tumors that also revealed a negative correlation between GR and tumor size and higher NR3C1 expression in densely granulated tumors., Conclusions: Although the associations between gene/protein expression and patients clinical features are not strong, they consistently show an evident trend in which higher receptor expression corresponds to more favorable clinical characteristics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kober, Rusetska, Mossakowska, Maksymowicz, Pękul, Zieliński, Styk, Kunicki, Działach, Witek and Bujko.)
- Published
- 2023
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23. Transcriptomic Classification of Pituitary Neuroendocrine Tumors Causing Acromegaly.
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Rymuza J, Kober P, Rusetska N, Mossakowska BJ, Maksymowicz M, Nyc A, Baluszek S, Zieliński G, Kunicki J, and Bujko M
- Subjects
- Humans, Transcriptome genetics, Growth Hormone metabolism, Gene Expression Profiling, Neuroendocrine Tumors complications, Neuroendocrine Tumors genetics, Neuroendocrine Tumors pathology, Adenoma genetics, Pituitary Neoplasms genetics, Acromegaly genetics, Acromegaly pathology
- Abstract
Acromegaly results from growth hormone hypersecretion, predominantly caused by a somatotroph pituitary neuroendocrine tumor (PitNET). Acromegaly-causing tumors are histologically diverse. Our aim was to determine transcriptomic profiles of various somatotroph PitNETs and to evaluate clinical implication of differential gene expression. A total of 48 tumors were subjected to RNA sequencing, while expression of selected genes was assessed in 134 tumors with qRT-PCR. Whole-transcriptome analysis revealed three transcriptomic groups of somatotroph PitNETs. They differ in expression of numerous genes including those involved in growth hormone secretion and known prognostic genes. Transcriptomic subgroups can be distinguished by determining the expression of marker genes. Analysis of the entire cohort of patients confirmed differences between molecular subtypes of tumors. Transcriptomic group 1 includes ~20% of acromegaly patients with GNAS mutations-negative, mainly densely granulated tumors that co-express GIPR and NR5A1 (SF-1). SF-1 expression was verified with immunohistochemistry. Transcriptomic group 2 tumors are the most common (46%) and include mainly GNAS -mutated, densely granulated somatotroph and mixed PitNETs. They have a smaller size and express favorable prognosis-related genes. Transcriptomic group 3 includes predominantly sparsely granulated somatotroph PitNETs with low GNAS mutations frequency causing ~35% of acromegaly. Ghrelin signaling is implicated in their pathogenesis. They have an unfavorable gene expression profile and higher invasive growth rate.
- Published
- 2022
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24. The Expression of Cell Cycle-Related Genes in USP8 -Mutated Corticotroph Neuroendocrine Pituitary Tumors and Their Possible Role in Cell Cycle-Targeting Treatment.
- Author
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Mossakowska BJ, Rusetska N, Konopinski R, Kober P, Maksymowicz M, Pekul M, Zieliński G, Styk A, Kunicki J, and Bujko M
- Abstract
Protein deubiquitinases USP8 and USP48 are known driver genes in corticotroph pituitary neuroendocrine tumors (PitNETs). USP8 mutations have pleiotropic effects that include notable changes in genes' expression. Genes involved in cell cycle regulation were found differentially expressed in mutated and wild-type tumors. This study aimed to verify difference in the expression level of selected cell cycle-related genes and investigate their potential role in response to cell cycle inhibitors. Analysis of 70 corticotroph PitNETs showed that USP8 -mutated tumors have lower CDKN1B , CDK6 , CCND2 and higher CDC25A expression. USP48 -mutated tumors have lower CDKN1B and CCND1 expression. A lower p27 protein level in mutated than in wild-type tumors was confirmed that may potentially influence the response to small molecule inhibitors targeting the cell cycle. We looked for the role of USP8 mutations or a changed p27 level in the response to palbociclib, flavopiridol and roscovitine in vitro using murine corticotroph AtT-20/D16v-F2 cells. The cells were sensitive to each agent and treatment influenced the expression of genes involved in cell cycle regulation. Overexpression of mutated Usp8 in the cells did not affect the expression of p27 nor the response to the inhibitors. Downregulating or upregulating p27 expression in AtT-20/D16v-F2 cells also did not affect treatment response.
- Published
- 2022
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25. CXCR4/ACKR3/CXCL12 axis in the lymphatic metastasis of vulvar squamous cell carcinoma.
- Author
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Rusetska N, Kowalski K, Zalewski K, Zięba S, Bidziński M, Goryca K, Kotowicz B, Fuksiewicz M, Kopczynski J, Bakuła-Zalewska E, Kowalik A, and Kowalewska M
- Subjects
- Chemokine CXCL12 metabolism, Female, Humans, Lymphatic Metastasis, Receptors, CXCR4 metabolism, Signal Transduction, Carcinoma, Squamous Cell, Receptors, CXCR metabolism, Vulvar Neoplasms
- Abstract
Aims: Vulvar squamous cell carcinoma (VSCC) spreads early and mainly locally via direct expansion into adjacent structures, followed by lymphatic metastasis to the regional lymph nodes (LNs). In the lymphatic metastasis, cancer cells bearing CXCR4 and ACKR3 (CXCR7) receptors are recruited to the LNs that produce the CXCL12 ligand. Our study aimed to assess the role of the CXCR4/ACKR3/CXCL12 axis in VSCC progression., Methods: Tumour and LN tissue samples were obtained from 46 patients with VSCC and 51 patients with premalignant vulvar lesions. We assessed CXCR4, ACKR3 and CXCL12 by immunohistochemistry (IHC) in the tissue samples. Additionally, CXCL12 levels were determined by ELISA in the sera of 23 patients with premalignant lesions, 37 with VSCC and 16 healthy volunteers., Results: CXCR4 and ACKR3 proteins were virtually absent in vulvar precancers, while in VSCC samples the IHC staining was strong. In the LNs of patients with VSCC, 98% of metastatic cells expressed CXCR4 and 85% expressed ACKR3. Neither CXCR4 nor ACKR3 presence was correlated with tumour human papilloma virus status. Few CXCL12-positive cells were found in the analysed tissue samples, but serum CXCL12 levels were significantly increased in both patients with premalignant vulvar lesions and with VSCC compared with healthy volunteers., Conclusions: It appears that during progression and lymphatic spread of VSCC, the CXCR4/ACKR3/CXCL12 axis is activated. Moreover, our data suggest that CXCR4 antagonists merit further attention as a possible therapeutic option in patients with VSCC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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26. Difference in miRNA Expression in Functioning and Silent Corticotroph Pituitary Adenomas Indicates the Role of miRNA in the Regulation of Corticosteroid Receptors.
- Author
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Mossakowska BJ, Kober P, Rusetska N, Boresowicz J, Maksymowicz M, Pękul M, Zieliński G, Styk A, Kunicki J, Mandat T, and Bujko M
- Subjects
- Corticotrophs metabolism, Humans, Receptors, Glucocorticoid metabolism, ACTH-Secreting Pituitary Adenoma genetics, Adenoma metabolism, MicroRNAs genetics, Pituitary Neoplasms genetics, Pituitary Neoplasms metabolism
- Abstract
Corticotroph pituitary adenomas commonly cause Cushing's disease (CD), but some of them are clinically silent. The reason why they do not cause endocrinological symptoms remains unclear. We used data from small RNA sequencing in adenomas causing CD ( n = 28) and silent ones ( n = 20) to explore the role of miRNA in hormone secretion and clinical status of the tumors. By comparing miRNA profiles, we identified 19 miRNAs differentially expressed in clinically functioning and silent corticotroph adenomas. The analysis of their putative target genes indicates a role of miRNAs in regulation of the corticosteroid receptors expression. Adenomas causing CD have higher expression of hsa-miR-124-3p and hsa-miR-135-5p and lower expression of their target genes NR3C1 and NR3C2 . The role of hsa-miR-124-3p in the regulation of NR3C1 was further validated in vitro using AtT-20/D16v-F2 cells. The cells transfected with miR-124-3p mimics showed lower levels of glucocorticoid receptor expression than control cells while the interaction between miR-124-3p and NR3C1 3' UTR was confirmed using luciferase reporter assay. The results indicate a relatively small difference in miRNA expression between clinically functioning and silent corticotroph pituitary adenomas. High expression of hsa-miR-124-3p in adenomas causing CD plays a role in the regulation of glucocorticoid receptor level and probably in reducing the effect of negative feedback mediated by corticosteroids.
- Published
- 2022
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27. RRM2 gene expression depends on BAF180 subunit of SWISNF chromatin remodeling complex and correlates with abundance of tumor infiltrating lymphocytes in ccRCC.
- Author
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Szarkowska J, Cwiek P, Szymanski M, Rusetska N, Jancewicz I, Stachowiak M, Swiatek M, Luba M, Konopinski R, Kubala S, Zub R, Kucharz J, Wiechno P, Siedlecki JA, Markowicz S, Sarnowska E, and Sarnowski TJ
- Abstract
About 40% of clear cell renal cell carcinoma (ccRCC) cases carry the pbrm1 mutation inactivating BAF180 subunit of the SWI/SNF chromatin remodeling complex (CRC). Here we show that the majority of transcriptomic changes appear at the stage I of ccRCC development. By contrast, the stage II ccRCC exhibits hyperactivation of DNA replication demonstrated by the overexpression of several genes, e.g., RRM1 and RRM2 genes encoding subunits of ribonucleotide reductase (RNR) complex. We found that the degree of RRM1 and RRM2 upregulation in ccRCC patients depends on pbrm1 mutation. We show that the BAF180 protein product of the PBRM1 gene directly binds to RRM1 and RRM2 loci . The BAF180 binding regions are targeted by regulatory proteins previously reported as SWI/SNF CRC interacting partners. BAF180 binding to RRMs loci correlates with enrichment of H3K27me3 in case of RRM1 and H3K14Ac on RRM2 , indicating the existence of differential regulatory mechanism controlling expression of these genes. We found that the strong overexpression of RRM2 in ccRCC patient samples correlates with T cell infiltration. Surprisingly, the majority of tumor infiltrating lymphocytes (TILs) consisted of CD4
+ T cells. Furthermore, we show that exhausted CD4+ T cells induced the expression of the RRM2 gene in the primary ccRCC cell line. Collectively, our results provide the link between PBRM1 loss, RRM2 expression and T cell infiltration, which may lead to the establishment of new treatment of this disease., Competing Interests: None., (AJCR Copyright © 2021.)- Published
- 2021
28. Succinate Dehydrogenase-Deficient Renal Cancer Featuring Fructose-1,6-Biphosphatase Loss, Pyruvate Kinase M2 Overexpression, and SWI/SNF Chromatin Remodeling Complex Aberrations: A Rare Case Report.
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Szymanski M, Rusetska N, Jancewicz I, Armatowska A, Ligaj M, Chrzan A, Hincza K, Kowalik A, Mika P, Kisiel M, Zolnierek J, Kosior J, Demkow T, Siedlecki JA, Sarnowski TJ, and Sarnowska E
- Subjects
- Adolescent, Chromatin Assembly and Disassembly, Fructose, Fructose-Bisphosphatase, Humans, Male, Neoplasm Recurrence, Local, Pyruvate Kinase genetics, Succinate Dehydrogenase genetics, Carcinoma, Renal Cell genetics, Kidney Neoplasms genetics
- Abstract
Succinate dehydrogenase (SDH)-deficient renal cancer is a rare renal cancer subtype recently accepted by the World Health Organization as a unique subtype of renal cell carcinoma (RCC). Here we report a case of 17-year-old man. The detailed evaluation indicated occurrence of the SDHB-deficient RCC. The genetic testing revealed no germline mutation in SDH genes. Immunohistochemistry showed SDHB deficiency, overexpression of pyruvate kinase M2 and dramatic downregulation of fructose-1,6-bisphosphatase metabolic enzymes, and unaltered levels of phosphorylated AMP-activated protein kinase and mammalian target of rapamycin. Strong upregulation of INI1 and BRG1 and overexpression of BAF180, subunits of SWI/SNF ATP-dependent chromatin remodeling complex, were also found. The identified tumor pathologically did not resemble clear cell renal cell carcinoma (ccRCC), but some metabolic alterations are common for both cancer types. Thus, we postulate that the phenotypical differences between ccRCC and SDHB-deficient RCC may be related to distinct molecular and metabolic alterations. IMPLICATIONS FOR PRACTICE: Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare renal tumor occurring even in young patients. Until now, in all described and genetically tested cases, mutations and deletions in SDH genes have been found. This article describes SDHB-deficient RCC without any germline mutations in SDH genes. Therefore, genetic analysis for germline mutations in SDH genes in SDH-deficient RCC, especially in young individuals, should be strongly recommended, although as of now it is not obligatory. This knowledge will allow improvement of patient monitoring including both disease recurrence and new cancer appearance., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)
- Published
- 2021
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29. PD-L1 Overexpression, SWI/SNF Complex Deregulation, and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4 + T Cells.
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Jancewicz I, Szarkowska J, Konopinski R, Stachowiak M, Swiatek M, Blachnio K, Kubala S, Oksinska P, Cwiek P, Rusetska N, Tupalska A, Zeber-Lubecka N, Grabowska E, Swiderska B, Malinowska A, Mikula M, Jagielska B, Walewski J, Siedlecki JA, Sarnowski TJ, Markowicz S, and Sarnowska EA
- Abstract
Growing tumors avoid recognition and destruction by the immune system. During continuous stimulation of tumor-infiltrating lymphocytes (TILs) by tumors, TILs become functionally exhausted; thus, they become unable to kill tumor cells and to produce certain cytokines and lose their ability to proliferate. This collectively results in the immune escape of cancer cells. Here, we show that breast cancer cells expressing PD-L1 can accelerate exhaustion of persistently activated human effector CD4
+ T cells, manifesting in high PD-1 and PD-L1 expression level son T cell surfaces, decreased glucose metabolism genes, strong downregulation of SWI/SNF chromatin remodeling complex subunits, and p21 cell cycle inhibitor upregulation. This results in inhibition of T cell proliferation and reduction of T cell numbers. The RNAseq analysis on exhausted CD4+ T cells indicated strong overexpression of IDO1 and genes encoding pro-inflammatory cytokines and chemokines. Some interleukins were also detected in media from CD4+ T cells co-cultured with cancer cells. The PD-L1 overexpression was also observed in CD4+ T cells after co-cultivation with other cell lines overexpressing PD-L1, which suggested the existence of a general mechanism of CD4+ T cell exhaustion induced by cancer cells. The ChIP analysis on the PD-L1 promoter region indicated that the BRM recruitment in control CD4+ T cells was replaced by BRG1 and EZH2 in CD4+ T cells strongly exhausted by cancer cells. These findings suggest that epi-drugs such as EZH2 inhibitors may be used as immunomodulators in cancer treatment.- Published
- 2021
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30. The SWI/SNF complex in eosinophilic and non eosinophilic chronic rhinosinusitis.
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Kowalik K, Waniewska-Leczycka M, Sarnowska E, Rusetska N, Ligaj M, Chrzan A, and Popko M
- Subjects
- Chronic Disease, Eosinophils, Humans, Nasal Polyps, Rhinitis, Sinusitis
- Abstract
Introduction: Chronic rhinosinusitis (CRS) can be classified as eosinophilic (eCRS) or non-eosinophilic (neCRS) based on infiltration type. The SWI/SNF complex may be involved in the pathophysiology of CRS., Aim: To assess the expression of the SWI/SNF complex in both CRS groups; to correlate blood eosinophil count (BEC), and histopathology eosinophil count (HPEC) with the SWI/SNF expression level in eCRS and neCRS., Materials and Methods: The study population consisted of 96 patients (68 eCRS, 28 neCRS). Immunohistochemical staining was performed on sinonasal mucosa for assessment of SWI/SNF protein expression. Type of tissue infiltration was assessed in samples obtained from examined groups (HPEC). The diagnostic value of eCRS was 10 cells/HPF (high power field). Complete blood count was analysed in order to calculate BEC., Results: BEC and HPEC correlated negatively with all the SWI/SNF subunits. HPEC and BEC correlated positively with clinical findings (L-M and SNOT-22), while SWI/SNF correlated negatively with clinical findings (L-M and SNOT-22)., Conclusions: The SWI/SNF was observed in both eCRS and neCRS, with lower expression in former. The meaning of its negative correlation with BEC, HPEC and clinical findings in eCRS group remains to be understood., (Copyright © 2021 Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale, Rome, Italy.)
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- 2021
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31. Invasive and Noninvasive Nonfunctioning Gonadotroph Pituitary Tumors Differ in DNA Methylation Level of LINE-1 Repetitive Elements.
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Rusetska N, Kober P, Król SK, Boresowicz J, Maksymowicz M, Kunicki J, Bonicki W, and Bujko M
- Abstract
Purpose: Epigenetic dysregulation plays a role in pituitary tumor pathogenesis. Some differences in DNA methylation were observed between invasive and noninvasive nonfunctioning gonadotroph tumors. This study sought to determine the role of DNA methylation changes in repetitive LINE-1 elements in nonfunctioning gonadotroph pituitary tumors., Methods: We investigated LINE-1 methylation levels in 80 tumors and normal pituitary glands with bisulfite-pyrosequencing. Expression of two LINE-1 open reading frames ( L1-ORF1 and L1-ORF2 ) was analyzed with qRT- PCR in tumor samples and mouse gonadotroph pituitary cells treated with DNA methyltransferase inhibitor. Immunohistochemical staining against L1-ORF1p was also performed in normal pituitary glands and tumors., Results: Hypomethylation of LINE-1 was observed in pituitary tumors. Tumors characterized by invasive growth revealed lower LINE-1 methylation level than noninvasive ones. LINE-1 methylation correlated with overall DNA methylation assessed with HM450K arrays and negatively correlated with L1-ORF1 and L1-ORF2 expression. Treatment of αT3-1 gonadotroph cells with 5-Azacytidine clearly increased the level of L1-ORF1 and L1-ORF2 mRNA; however, its effect on LβT2 cells was less pronounced. Immunoreactivity against L1-ORF1p was higher in tumors than normal tissue. No difference in L1-ORF1p expression was observed in invasive and noninvasive tumors., Conclusion: Hypomethylation of LINE-1 is related to invasive growth and influences transcriptional activity of transposable elements.
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- 2021
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32. Differential microRNA Expression in USP8 -Mutated and Wild-Type Corticotroph Pituitary Tumors Reflect the Difference in Protein Ubiquitination Processes.
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Bujko M, Kober P, Boresowicz J, Rusetska N, Zeber-Lubecka N, Paziewska A, Pekul M, Zielinski G, Styk A, Kunicki J, Ostrowski J, Siedlecki JA, and Maksymowicz M
- Abstract
Background: USP8 mutations are the most common driver changes in corticotroph pituitary tumors. They have direct effect on cells' proteome through disturbance of ubiquitination process and also influence gene expression. The aim of this study was to compare microRNA profiles in USP8 -mutated and wild-type tumors and determine the probable role of differential microRNA expression by integrative microRNA and mRNA analysis., Methods: Patients with Cushing's disease ( n = 28) and silent corticotroph tumors ( n = 20) were included. USP8 mutations were identified with Sanger sequencing. MicroRNA and gene expression was determined with next-generation sequencing., Results: USP8 -mutated patients with Cushing's disease showed higher rate of clinical remission and trend towards lower tumor volume than wild-type patients. Comparison of microRNA profiles of USP8 -mutated and wild-type tumors revealed 68 differentially expressed microRNAs. Their target genes were determined by in silico prediction and microRNA/mRNA correlation analysis. GeneSet Enrichment analysis of putative targets showed that the most significantly overrepresented genes are involved in protein ubiquitination-related processes. Only few microRNAs influence the expression of genes differentially expressed between USP8 -mutated and wild-type tumors., Conclusions: Differences in microRNA expression in corticotropinomas stratified according to USP8 status reflect disturbed ubiquitination processes, but do not correspond to differences in gene expression between these tumors.
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- 2021
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33. Inflammatory Proteins HMGA2 and PRTN3 as Drivers of Vulvar Squamous Cell Carcinoma Progression.
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Fatalska A, Rusetska N, Bakuła-Zalewska E, Kowalik A, Zięba S, Wroblewska A, Zalewski K, Goryca K, Domański D, and Kowalewska M
- Abstract
Current knowledge on the biology of squamous cell vulvar carcinoma (VSCC) is limited. We aimed to identify protein markers of VSCC tumors that would permit to stratify patients by progression risk. Early-stage tumors from patients who progressed (progVSCC) and from those who were disease-free (d-fVSCC) during follow-up, along with normal vulvar tissues were examined by mass spectrometry-based proteomics. Differentially expressed proteins (DEPs) were then verified in solid tissues and blood samples of patients with VSCC tumors and vulvar premalignant lesions. In progVSCC vs. d-fVSCC tumors, the immune response was the most over-represented Gene Ontology category for the identified DEPs. Pathway profiling suggested bacterial infections to be linked to aggressive VSCC phenotypes. High Mobility Group AT-Hook 2 (HMGA2) and Proteinase 3 (PRTN3) were revealed as proteins predicting VSCC progression. HMGA2 and PRTN3 abundances are associated with an aggressive phenotype, and hold promise as markers for VSCC patient stratification. It appears that vulvovaginal microflora disturbances trigger an inflammatory response contributing to cancer progression, suggesting that bacterial rather than viral infection status should be considered in the development of targeted therapies in VSCC.
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- 2020
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34. The Search of miRNA Related to Invasive Growth of Nonfunctioning Gonadotropic Pituitary Tumors.
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Boresowicz J, Kober P, Rusetska N, Maksymowicz M, Paziewska A, Dąbrowska M, Zeber-Lubecka N, Kunicki J, Bonicki W, Ostrowski J, Siedlecki JA, and Bujko M
- Abstract
Purpose: Nonfunctioning gonadotropic pituitary neuroendocrine tumors (PitNETs) are among the most frequent neoplasms of pituitary gland. Although PitNETs are commonly considered benign, a notable part of patients suffer from tumor recurrence after treatment. Invasive growth of pituitary tumor is among the most important prognostic factors. Since molecular features of invasiveness are of potential clinical usefulness, this study was aimed to verify whether invasive and noninvasive nonfunctioning gonadotropic PitNETs differ in the miRNA expression profile and whether the differences could provide a possible molecular classifier., Methods: miRNA profiles were determined in 20 patients (11 invasive and 9 noninvasive tumors) using next-generation sequencing. The expression of selected miRNAs was assessed in the independent cohort of 80 patients with qRT-PCR., Results: When miRNA profiles of invasive and noninvasive tumors were compared, 29 miRNAs were found differentially expressed. Hsa-miR-184, hsa-miR-181a-2-3p, hsa-miR-93-3p, hsa-miR-574-5p, hsa-miR-185-5p, and hsa-miR-3200-5p showed a potential clinical value according to ROC curve analysis. Unfortunately, differential expression of only hsa-miR-185-5p was confirmed in the validation cohort, with AUG at 0.654., Conclusion: Differences in miRNAs expression profiles in invasive and noninvasive gonadotropic PitNETs are slight and the level of miRNA expression seems not to be applicable as useful classifier of tumor invasiveness., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2020 Joanna Boresowicz et al.)
- Published
- 2020
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35. The expression of bitter taste receptor TAS2R38 in patients with chronic rhinosinusitis.
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Zborowska-Piskadło K, Stachowiak M, Rusetska N, Sarnowska E, Siedlecki J, and Dżaman K
- Subjects
- Cell Line, Tumor, Chronic Disease, Humans, Immunohistochemistry, Lipopolysaccharides pharmacology, Nasal Polyps metabolism, Taste, Cell Nucleus metabolism, Receptors, G-Protein-Coupled metabolism, Rhinitis metabolism, Sinusitis metabolism
- Abstract
Chronic rhinosinusitis (CRS) is a frequent disease with high social impact and multifactorial pathogenesis. Recently, the bitter taste receptor TAS2R38 has been described to play a role in upper airway innate mucosal defense. The aim was to determine the localization and expression of the TAS2R38 in the selected cell lines and tissue collected from patient suffered from CRS as well as to correlate the results with clinical data. Moreover, the purpose was the estimation of the TAS2R38 distribution changes during acute and CRS. Forty-two patients undergoing nasal surgery were enrolled in the study. The TAS2R38 expression was assessed in the collected tissues using immunohistochemistry and immunocytochemistry methods. The western blot analysis was performed on human cell lines HeLa, MCF7, MDA-MB-231 to assess the location of the TAS2R38 protein. Moreover, the HeLa cell line was used as a model of acute inflammation induces by lipopolysaccharide. Immunohistochemistry analysis displayed a statistically significant difference of TAS2R38 level in the patients with CRS compared to healthy control and was different in CRS with and without nasal polyps. The results showed the abundance of TAS2R38 receptor in the cell nucleus in patients with CRS and cell lines. The variance in TAS2R38 receptor expression in two CRS types suggests their different pathogenesis. The first time in literature, we confirmed the presence of plasma membrane TAS2R38 receptor in the cell nuclei in CRS as well as in cell lines, what strongly suggests the different than membrane TAS2R38 function.
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- 2020
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36. Somatic Mutation Profiling in Premalignant Lesions of Vulvar Squamous Cell Carcinoma.
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Zięba S, Pouwer AW, Kowalik A, Zalewski K, Rusetska N, Bakuła-Zalewska E, Kopczyński J, Pijnenborg JMA, de Hullu JA, and Kowalewska M
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Middle Aged, Carcinoma, Squamous Cell genetics, Mutation genetics, Precancerous Conditions genetics, Vulvar Neoplasms genetics
- Abstract
Vulvar squamous cell carcinoma (VSCC) originates from the progression of either a high-grade squamous intraepithelial lesion (HSIL) or differentiated-type vulvar intraepithelial neoplasia (dVIN), often in a background of lichen sclerosus (LS). The mechanisms leading to the progression of these premalignant lesions to VSCC are elusive. This study aims to identify pathogenic mutations implicated in VSCC development. Using next-generation sequencing, 38 HSIL, 19 dVIN, 20 LS, of which 10 were solitary lesions and 10 with adjacent VSCC, and 10 VSCC adjacent to LS, were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific). Pathogenic mutations of TP53 were the most common genetic alterations identified in 53% and 24% of dVIN and HSIL cases, respectively, followed by CDKN2A (p16) mutated in 42% and 0% of dVIN and HSIL, respectively. Seven (70%) and three (30%) of 10 cases of VSCC associated with LS carried TP53 and CDKN2A mutations, respectively, whereas neither solitary LS nor LS associated with VSCC cases harbored mutations in these genes. It appears that TP53 mutations are early events during VSCC carcinogenesis, being present in both HSIL and dVIN lesions. Our preliminary data do not support a genetic background for the notion of LS as the VSCC premalignant lesion.
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- 2020
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37. SWI/SNF chromatin remodeling complex and glucose metabolism are deregulated in advanced bladder cancer.
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Stachowiak M, Szymanski M, Ornoch A, Jancewicz I, Rusetska N, Chrzan A, Demkow T, Siedlecki JA, Sarnowski TJ, and Sarnowska E
- Subjects
- AMP-Activated Protein Kinases genetics, AMP-Activated Protein Kinases metabolism, Aged, Carrier Proteins genetics, Carrier Proteins metabolism, Cell Line, Tumor, Chromatin Assembly and Disassembly, Epithelial-Mesenchymal Transition genetics, Female, Fructose-Bisphosphatase genetics, Fructose-Bisphosphatase metabolism, Gene Expression Regulation, Neoplastic, Humans, Male, Membrane Proteins genetics, Membrane Proteins metabolism, SMARCB1 Protein genetics, Thyroid Hormones genetics, Thyroid Hormones metabolism, Transcription Factors genetics, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms mortality, Urinary Bladder Neoplasms pathology, Thyroid Hormone-Binding Proteins, Glucose metabolism, SMARCB1 Protein metabolism, Transcription Factors metabolism, Urinary Bladder Neoplasms metabolism
- Abstract
Bladder cancer (BC) is a frequently diagnosed malignancy affecting predominantly adult and elderly populations. It is expected that due to the longer life time, BC will become even more frequent in the future; thus in consequence, it will represent serious health problem of older society part. The treatment of advanced BC is mostly ineffective due to its very aggressive behavior. So far, no effective targeted therapy is used for BC treatment. Here, we found that BC is characterized by lower protein levels of BRM, INI1, and BAF155 main subunits of SWI/SNF chromatin remodeling complex (CRC) which is involved in global control of gene expression and influences various important cellular processes like: cell cycle control, apoptosis, DNA repair, etc. Moreover, the expression of SMARCA2, a BRM encoding gene, strongly correlated with BC metastasis and expression of such metabolic genes as PKM2 and PRKAA1. Furthermore, the analysis of T24 and 5637 commonly used BC cell lines revealed different expression levels of metabolic genes including FBP1 gene encoding Frutose-1,6-Bisphosphatase, an enzyme controlling glycolysis flux and gluconeogenesis. The tested BC cell lines exhibited various molecular and metabolic alterations as well as differential glucose uptake, growth rate, and migration potential. We have shown that BRM subunit is involved in the transcriptional control of genes encoding metabolic enzymes. Moreover, we found that the FBP1 expression level and the SWI/SNF CRCs may serve as markers of molecular subtypes of BC. Collectively, this study may provide a new knowledge about the molecular and metabolic BC subtypes which likely will be of high importance for the clinic in the future., (© 2020 The Authors. IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology.)
- Published
- 2020
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38. DNA Methylation Influences miRNA Expression in Gonadotroph Pituitary Tumors.
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Boresowicz J, Kober P, Rusetska N, Maksymowicz M, Paziewska A, Dąbrowska M, Zeber-Lubecka N, Kunicki J, Bonicki W, Ostrowski J, Siedlecki JA, and Bujko M
- Abstract
microRNAs are involved in pathogenesis of cancer. DNA methylation plays a role in transcription of miRNA-encoding genes and may contribute to changed miRNA expression in tumors. This issue was not investigated in pituitary neuroendocrine tumors (PitNETs) previously. DNA methylation patterns, assessed with HumanMethylation450K arrays in 34 PitNETs and five normal pituitaries, were used to determine differentially methylated CpGs located at miRNA genes. It showed aberrant methylation in regions encoding for 131 miRNAs. DNA methylation data and matched miRNA expression profiles, determined with next-generation sequencing (NGS) of small RNAs, were correlated in 15 PitNETs. This showed relationship between methylation and expression levels for 12 miRNAs. DNA methylation and expression levels of three of them ( MIR145 , MIR21 , and MIR184 ) were determined in the independent group of 80 tumors with pyrosequencing and qRT-PCR and results confirmed both aberrant methylation in PitNETs and correlation between methylation and expression. Additionally, in silico target prediction was combined with analysis of established miRNA profiles and matched mRNA expression pattern, assessed with amplicon-based NGS to indicate putative target genes of epigenetically deregulated miRNAs. This study reveals aberrant DNA methylation in miRNA-encoding genes in gonadotroph PitNETs. Methylation changes affect expression level of miRNAs that regulate putative target genes with tumorigenesis-relevant functions.
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- 2020
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39. Role of chromatin remodeling complex SWI/SNF and VDR in chronic rhinosinusitis.
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Kowalik K, Waniewska-Łęczycka M, Sarnowska E, Rusetska N, Sierdziński J, and Zagor M
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- Case-Control Studies, Humans, STAT1 Transcription Factor, Chromatin Assembly and Disassembly, DNA-Binding Proteins genetics, Receptors, Calcitriol genetics, Sinusitis genetics, Transcription Factors genetics
- Abstract
Background: The SWI/SNF (SWItch/sucrose non-fermentable) chromatin remodeling complex enables glucocorticoid receptor (GR) and vitamin D receptor (VDR) to function correctly and is engaged in inflammation response. The SWI/SNF may play an important role in chronic rhinosinusitis (CRS)., Objectives: The aim of this study was to assess the following: 1) the gene and protein expression of the SWI/SNF complex subunits in sinonasal mucosa; 2) relation of SWI/SNF complex and VDR expression; and 3) correlation with clinical data., Material and Methods: The study population consisted of 52 subjects with CRS without nasal polyps, 55 with CRS with nasal polyps and 59 controls. The SWI/SNF protein expression level was analyzed in immunohistochemical (IHC) staining. Human nasal epithelial cells (HNECs) was stimulated using lipopolysaccharide (LPS), Staphylococcal enterotoxin B (SEB) and vitamin D3 (vitD3) in vitro. The transcript level of the SWI/SNF subunits was measured with polymerase chain reaction (PCR)., Results: In the control group, the intensity of the IHC staining for SWI/SNF subunits was significantly higher than in both groups of patients with CRS (p < 0.05). A positive correlation of the SWI/SNF protein expression was noticed with VDR expression level (p < 0.043). Association between SWI/SNF protein expression level and allergy, neutrophils and body mass index (BMI) has been observed (p < 0.05). The decreased transcript level of the SWI/SNF subunits genes in HNECs was observed after LPS stimulation and increased after vitD3 stimulation., Conclusions: The SWI/SNF complex may influence CRS through steroid hormone signaling and VDR. Thus, modification in therapy may be mandatory in patients with CRS and altered SWI/SNF signaling, reflecting resistance to steroids treatment.
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- 2020
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40. USP8 mutations in corticotroph adenomas determine a distinct gene expression profile irrespective of functional tumour status.
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Bujko M, Kober P, Boresowicz J, Rusetska N, Paziewska A, Dąbrowska M, Piaścik A, Pękul M, Zieliński G, Kunicki J, Bonicki W, Ostrowski J, Siedlecki JA, and Maksymowicz M
- Subjects
- Adult, Aged, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins metabolism, Connexin 43 genetics, Connexin 43 metabolism, Female, GTPase-Activating Proteins genetics, GTPase-Activating Proteins metabolism, Humans, Immunohistochemistry, Male, Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, T-Box Domain Proteins genetics, T-Box Domain Proteins metabolism, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Zinc Finger Protein Gli2 genetics, Zinc Finger Protein Gli2 metabolism, ACTH-Secreting Pituitary Adenoma genetics, ACTH-Secreting Pituitary Adenoma metabolism, Endopeptidases genetics, Endosomal Sorting Complexes Required for Transport genetics, Mutation genetics, Pituitary Neoplasms genetics, Pituitary Neoplasms metabolism, Ubiquitin Thiolesterase genetics
- Abstract
Objective: Pituitary corticotroph adenomas commonly cause Cushing's disease (CD) but part of these tumours are hormonally inactive (silent corticotroph adenomas, SCA). USP8 mutations are well-known driver mutations in corticotrophinomas. Differences in transcriptomic profiles between functioning and silent tumours or tumours with different USP8 status have not been investigated., Design and Methods: Forty-eight patients (28 CD, 20 SCA) were screened for USP8 mutations with Sanger sequencing. Twenty-four patients were included in transcriptomic profiling with Ampliseq Transcriptome Human Gene Expression Core Panel. The entire patients group was included in qRT-PCR analysis of selected genes expression. Immunohistochemistry was used for visualization of selected protein., Results: We found USP8 mutation in 15 patients with CD and 4 SCAs. USP8 mutations determine molecular profile of the tumours as showed by hierarchical clustering and identification of 1648 genes differentially expressed in USP8-mutated and USP8-wild-type tumours. Mutations affect many molecular pathways as observed in Gene Set Enrichment analysis. USP8-mutated adenomas showed higher level of POMC, CDC25A, MAPK4 but lower level of CCND2, CDK6, CDKN1B than USP8-wt tumours. Eighty-seven genes differentially expressed between CD-related adenomas and SCAs were found, including those involved in cell signalling (GLI2, DLC1, TBX2, RASSF6), cell adhesion (GJA1, CDH6), ion transport (KCNN4, KCNJ5) and GABA signalling (GABBR2, GABRD)., Conclusion: USP8 mutations occur in functioning and silent corticotrophinomas. They have pleiotropic effect, not limited to EGFR signalling, and affect expression levels of many genes involved in different pathways. Expression of GABA-related genes GABBR2, GNAL, GABARD and KCNJ5 correspond to functional status of the tumours.
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- 2019
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41. The Role of Aberrant DNA Methylation in Misregulation of Gene Expression in Gonadotroph Nonfunctioning Pituitary Tumors.
- Author
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Kober P, Boresowicz J, Rusetska N, Maksymowicz M, Paziewska A, Dąbrowska M, Kunicki J, Bonicki W, Ostrowski J, Siedlecki JA, and Bujko M
- Abstract
Gonadotroph nonfunctioning pituitary adenomas (NFPAs) are common intracranial tumors, but the role of aberrant epigenetic regulation in their development remains poorly understood. In this study, we investigated the effect of impaired CpG methylation in NFPAs. We determined DNA methylation and transcriptomic profiles in 32 NFPAs and normal pituitary sections using methylation arrays and sequencing, respectively. Ten percent of differentially methylated CpGs were correlated with gene expression, and the affected genes are involved in a variety of tumorigenesis-related pathways. Different proportions of gene body and promoter region localization were observed in CpGs with negative and positive correlations between methylation and gene expression, and different proportions of CpGs were located in 'open sea' and 'shelf/shore' regions. The expression of ~8% of genes differentially expressed in NFPAs was related to aberrant methylation. Methylation levels of seven CpGs located in the regulatory regions of FAM163A , HIF3A and PRSS8 were determined by pyrosequencing, and gene expression was measured by qRT-PCR and immunohistochemistry in 83 independent NFPAs. The results clearly confirmed the negative correlation between methylation and gene expression for these genes. By identifying which aberrantly methylated CpGs affect gene expression in gonadotrophinomas, our data confirm the role of aberrant methylation in pathogenesis of gonadotroph NFPAs.
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- 2019
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42. Role of Vitamin D and Its Receptors in the Pathophysiology of Chronic Rhinosinusitis.
- Author
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Tomaszewska M, Sarnowska E, Rusetska N, Kowalik K, Sierdzinski J, Siedlecki JA, Badmaev V, Stohs SJ, and Popko M
- Subjects
- 25-Hydroxyvitamin D3 1-alpha-Hydroxylase blood, Adolescent, Adult, Aged, Aged, 80 and over, Calcifediol blood, Chronic Disease, Dietary Supplements, Female, Humans, Male, Middle Aged, Nasal Polyps complications, Prospective Studies, Rhinitis complications, Rhinitis therapy, Sinusitis complications, Sinusitis therapy, Steroid Hydroxylases blood, Vitamin D administration & dosage, Young Adult, Nasal Polyps blood, Receptors, Calcitriol blood, Rhinitis blood, Sinusitis blood, Vitamin D blood
- Abstract
Objectives: Chronic rhinosinusitis (CRS) is a disease that represents a challenging therapeutic problem. Vitamin D and its receptors (VDR) are involved in the regulation of the immune system and may play role in CRS. Objectives of this study were to assess the relationships between the total concentration of vitamin D (25VD3) in sera, vitamin D receptor (VDR) expression, 1α-hydroxylase expression, and clinical data, including age, gender, Sino-Nasal Outcome Test (SNOT-22), computerized tomography (CT) scan, allergy status, and vitamin D supplementation in CRS patients with (CRSwNP) and without nasal polyps (CRSsNP), and in a control group., Methods: The studied group comprised 52 patients with CRS without nasal polyps (sNP), 55 with CRS with nasal polyps (wNP), and 59 in the control group. The endpoints were determined by appropriate methods. We conducted immunohistochemical staining of gathered tissue from the ostiomeatal complex for determination of VDR and 1α-hydroxylase. Analytical results were compared with clinical data as already noted., Results: A decrease in VDR nuclear staining occurred in CRS patients as compared to controls. Insignificant differences were observed in 1α-hydroxylase, expression in all studied groups, while VDR and cytochrome CYP27B1 protein expression (1α-hydroxylase) correlated with clinical data., Conclusions: The data provide evidence that indicates that vitamin D and its receptor and enzymes may play a role in CRS.
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- 2019
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43. Advanced adenoid cystic carcinoma (ACC) is featured by SWI/SNF chromatin remodeling complex aberrations.
- Author
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Jagielska B, Sarnowska E, Rusetska N, Jancewicz I, Durzynska M, Kubala S, Chmielik E, Paul P, Rutkowski T, Sarnowski TJ, and Siedlecki JA
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Adenoid Cystic genetics, Carcinoma, Adenoid Cystic metabolism, Female, Gene Expression Profiling, Humans, Male, Middle Aged, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Receptors, Androgen genetics, Transcription Factors genetics, Transcriptome, Young Adult, Carcinoma, Adenoid Cystic pathology, Chromatin Assembly and Disassembly, Transcription Factors metabolism
- Abstract
Purpose: Adenoid cystic carcinoma (ACC) is a rare neurotropic cancer with slow progression occurring in salivary glands and less frequently in other body parts. ACC is featured by hyperchromatic nuclei and various mutations in genes encoding chromatin-related machineries. The ACC treatment is mainly limited to the radical surgery and radiotherapy while the chemotherapy remains ineffective. As the knowledge about molecular basis of ACC development is limited, we investigated here the molecular features of this disease., Patients and Methods: This study included 50 patients with ACC. Transcript profiling of available ACC samples vs normal salivary gland tissue, quantitative real-time PCR (qRT-PCR) transcript level measurements and the immunohistochemistry (IHC) for SWI/SNF chromatin remodeling complex (CRC) subunits and androgen receptor on surgery-derived paraffin-embedded samples were performed., Results: Transcriptomic study followed by Gene Ontology classification indicated alteration of chromatin-related processes, including downregulated transcript levels of main SWI/SNF CRC subunits and elevated expression of BRM ATPase-coding SMARCA2 gene in ACC. Subsequent IHC indicated broad accumulation of BRM ATPase and several SWI/SNF subunits, suggesting affected control of their protein level in ACC. The IHC revealed ectopic, heterogeneous expression of androgen receptor (AR) in some ACC cells., Conclusions: Our study indicated that ACC features aberrant expression of genes controlling chromatin status and structure. We found that the balance between SWI/SNF classes is moved towards the BRM ATPase-containing complex in ACC. As BRM is known to be involved in chemoresistance in cancer cells, this observation may be the likely explanation for ACC chemoresistance.
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- 2019
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44. DNA methylation profiling in nonfunctioning pituitary adenomas.
- Author
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Kober P, Boresowicz J, Rusetska N, Maksymowicz M, Goryca K, Kunicki J, Bonicki W, Siedlecki JA, and Bujko M
- Subjects
- Adenoma pathology, Adult, Aged, Aged, 80 and over, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Pituitary Neoplasms pathology, Promoter Regions, Genetic, Adenoma genetics, DNA Methylation genetics, Pituitary Neoplasms genetics
- Abstract
Nonfunctioning pituitary adenomas (NFPAs) are among the most frequent intracranial tumors but their molecular background, including changes in epigenetic regulation, remains poorly understood. We performed genome-wide DNA methylation profiling of 34 NFPAs and normal pituitary samples. Methylation status of the selected genomic regions and expression level of corresponding genes were assessed in a group of 75 patients. NFPAs exhibited distinct global methylation profile as compared to normal pituitary. Aberrant DNA methylation appears to contribute to deregulation of the cancer-related pathways as shown by preliminary functional analysis. Promoter hypermethylation and decreased expression level of SFN, STAT5A, DUSP1, PTPRE and FGFR2 was confirmed in the enlarged group of NFPAs. Difference in the methylation profiles between invasive and non-invasive NFPAs is very slight. Nevertheless, invasiveness-related aberrant epigenetic deregulation of the particular genes was found including upregulation of ITPKB and downregulation CNKSR1 in invasive tumors., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
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45. Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets.
- Author
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Zięba S, Kowalik A, Zalewski K, Rusetska N, Goryca K, Piaścik A, Misiek M, Bakuła-Zalewska E, Kopczyński J, Kowalski K, Radziszewski J, Bidziński M, Góźdź S, and Kowalewska M
- Subjects
- AMP-Activated Protein Kinase Kinases, Adult, Aged, Aged, 80 and over, Antibiotics, Antineoplastic pharmacology, Antineoplastic Agents pharmacology, Benzamides, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell virology, Cell Line, Tumor, Cell Survival drug effects, Class I Phosphatidylinositol 3-Kinases genetics, Cyclin-Dependent Kinase Inhibitor p16, DNA Mutational Analysis, Disease-Free Survival, Everolimus pharmacology, F-Box-WD Repeat-Containing Protein 7 genetics, Female, GTP-Binding Protein alpha Subunits, Gq-G11 genetics, High-Throughput Nucleotide Sequencing, Humans, Janus Kinase 3 genetics, Middle Aged, Morpholines pharmacology, Mutation, PTEN Phosphohydrolase genetics, Papillomaviridae, Papillomavirus Infections complications, Phosphatidylinositol 3-Kinase metabolism, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases genetics, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins p21(ras) genetics, Pyrimidines, Receptor, Fibroblast Growth Factor, Type 3 genetics, Signal Transduction drug effects, Signal Transduction genetics, Sirolimus pharmacology, Smad4 Protein genetics, TOR Serine-Threonine Kinases metabolism, Vulvar Neoplasms metabolism, Vulvar Neoplasms virology, fms-Like Tyrosine Kinase 3 genetics, Carcinoma, Squamous Cell genetics, Cyclin-Dependent Kinase Inhibitor p18 genetics, DNA, Neoplasm analysis, Tumor Suppressor Protein p53 genetics, Vulvar Neoplasms genetics
- Abstract
Background: Vulvar squamous cell carcinoma (VSCC) constitutes over 90% of vulvar cancer. Its pathogenesis can follow two different pathways; high risk human papillomavirus (hrHPV)-dependent and HPV-independent. Due to the rarity of VSCC, molecular mechanisms underlying VSCC development remain largely unknown. The study aimed to identify pathogenic mutations implicated in the two pathways of VSCC development., Methods: Using next generation sequencing, 81 VSCC tumors, 52 hrHPV(+) and 29 hrHPV(-), were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific)., Results: Mutations of TP53 (46% and 41%, of hrHPV(+) and hrHPV(-) cases respectively) and CDKN2A (p16) (25% and 21%, of hrHPV(+) and hrHPV(-) cases respectively) were the most common genetic alterations identified in VSCC tumors. Further mutations were identified in PIK3CA, FBXW7, HRAS, FGFR3, STK11, AKT1, SMAD4, FLT3, JAK3, GNAQ, and PTEN, albeit at low frequencies. Some of the identified mutations may activate the PI3K/AKT/mTOR pathway. The activation of mTOR was confirmed in the vast majority of VSCC samples by immunohistochemical staining., Conclusions: Detecting pathogenic mutations in 13/50 genes examined at comparable frequencies in hrHPV(+) and hrHPV(-) tumors suggest that genetic mechanisms of the two routes of VSCC pathogenesis may be similar, despite being initiated from different premalignant lesions. Importantly, our data provide a rationale for new anti-VSCC therapies targeting the PI3K/AKT/mTOR pathway., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
46. Telomere length and TERT abnormalities in pituitary adenomas.
- Author
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Boresowicz J, Kober P, Rusetska N, Maksymowicz M, Goryca K, Kunicki J, Bonicki W, and Bujko M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, DNA Methylation, Female, Gene Dosage, Gene Expression Regulation, Neoplastic genetics, Genome-Wide Association Study, Humans, Incidence, Male, Middle Aged, Mutation, Missense genetics, RNA, Messenger biosynthesis, Young Adult, Adenoma genetics, Adenoma pathology, Pituitary Neoplasms genetics, Pituitary Neoplasms pathology, Telomerase genetics, Telomere pathology
- Abstract
Objectives: Pituitary adenomas (PAs) are among the most frequent intracranial tumors in humans. Abnormal telomerase activity and telomere lengthening are features of tumor cells. They may result from mutations in TERT promoter region, gene amplification or aberrant DNA methylation pattern. Such changes were found in variety of tumors including those of brain. Aim of the study was to evaluate the incidence of TERT abnormalities and to assess their role in telomere lengthening in PAs., Methods: Study involved 101 patients with PA including both nonfunctioning and functioning subtypes. Telomerase length as well as TERT mRNA level and gene amplification were estimated using quantitative PCR (qPCR). Promoter mutations were assessed using Sanger sequencing. The results from genome-wide DNA methylation profiling with HumanMethylation 450K (Illumina) were used for the analysis of TERT locus., Results: Variable telomere length was observed in patients, however no relationship with clinicopathological features was found. We observed a missense variant in TERT promoter in one patient only whereas increased TERT copy number were identified in 6 patients (5.6%). However no relationship between these results and telomere length or TERT expression was found. DNA methylation at TERT locus was not found to be changed when adenoma samples and normal tissue sections were compared., Conclusion: The results indicate that telomerase abnormalities do not play a role in pathogenesis of pituitary tumors.
- Published
- 2018
47. Evaluation of the role of downregulation of SNF5/INI1 core subunit of SWI/SNF complex in clear cell renal cell carcinoma development.
- Author
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Sarnowska E, Szymanski M, Rusetska N, Ligaj M, Jancewicz I, Cwiek P, Skrodzka M, Leszczynski M, Szarkowska J, Chrzan A, Stachowiak M, Steciuk J, Maassen A, Galek L, Demkow T, Siedlecki JA, and Sarnowski TJ
- Abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by stabilization of hypoxia-inducible factor (HIF1), and mutations in von Hippel-Lindau ( VHL ) gene. Additionally, in about 40% of ccRCC cases the mutation in PBRM1 ( POLYBROMO1 ) gene coding for a non-core subunit of SWI/SNF chromatin remodeling complex was found suggesting potential impairment of this complex function in ccRCC. In this study we assessed the extent to which the core SWI/SNF complex subunit - INI1 (hSNF5/SMARCB1) is affected in ccRCC and whether it has any consequences on the development of this type of cancer. The evaluation of INI1 protein level in samples from 50 patients with diagnosed ccRCC, including three displaying rhabdoid features, showed the INI1 positive staining in rhabdoid cells while the conventional ccRCC cells exhibited reduced INI1 level. This indicated the rhabdoid component of ccRCC as distinct from other known rhabdoid tumors. The reduced INI1 protein level observed in all conventional ccRCC cases used in this study correlated with decreased SMARCB1 gene expression at the transcript level. Consistently, the overexpression of INI1 protein in A498 ccRCC cell line resulted in the elevation of endogenous SMARCB1 transcript level indicating that the INI1-dependent regulatory feedback loop controlling expression of this gene is affected in ccRCC Moreover, the set of INI1 target genes including i.e. CXCL12/CXCR7/CXCR4 chemokine axis was identified to be affected in ccRCC. In summary, we demonstrated that the inactivation of INI1 may be of high importance for ccRCC development and aggressiveness., Competing Interests: None.
- Published
- 2017
48. Downregulation of PTPRH (Sap-1) in colorectal tumors.
- Author
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Bujko M, Kober P, Statkiewicz M, Mikula M, Grecka E, Rusetska N, Ligaj M, Ostrowski J, and Siedlecki JA
- Subjects
- Adult, Aged, Aged, 80 and over, Cell Line, Tumor, Colorectal Neoplasms pathology, Female, Gene Expression Regulation, Neoplastic, HT29 Cells, Humans, Male, Middle Aged, Promoter Regions, Genetic, Receptor-Like Protein Tyrosine Phosphatases, Class 3 genetics, Colorectal Neoplasms genetics, DNA Methylation genetics, Epigenesis, Genetic
- Abstract
Tyrosine phosphorylation is one of the basic mechanisms for signal transduction in the cell. Receptors exhibiting tyrosine kinase activity are widely involved in carcinogenesis and are negatively regulated by receptor protein tyrosine phosphatases (RPTP). Genes encoding different RPTPs are affected by aberrant epigenetic regulation in cancer. PTPRH (SAP-1) has been previously described to be overexpressed in colorectal cancer (CRC) and classified as an oncogenic factor. Previous microarray-based mRNA expression comparison of colorectal adenomas (AD), CRC and normal mucosa samples (NM) demonstrated that PTPRH tumor expression is the most reduced of all RPTP genes. qRT-PCR validation revealed gene downregulation for CRC (7.6-fold-change; P<0.0001) and AD (3.4-fold-change; P<0.0001) compared to NM. This was confirmed by immunohistochemical staining of tumor and NM sections as pronounced decrease of protein expression was observed in CRCs compared to the corresponding normal tissue. DNA methylation of two PTPRH promoter fragments was analyzed by pyrosequencing in a group of CRC, and AD patients as well as NM samples and CRC cell lines. The mean DNA methylation levels of these two regions were significantly higher in CRC than in NM. Both regions were highly methylated in SW480 and HCT116 cell lines contrary to unmethylated HT29 and COLO205. Cell lines with highly methylated promoters notably showed lower PTPRH expression levels, lower RNA II polymerase concentrations and higher levels of H3K27 trimethylation in the promoter and gene body, measured by chromatin immunoprecipitation. Cells were cultured with 5-aza-deoxycitidine and an increase in PTPRH expression was observed in SW480 and HCT116, whereas this was unchanged in the unmethylated cell lines. The results indicate that PTPRH is downregulated in colorectal tumors and its expression is epigenetically regulated via DNA methylation and chromatin modifications.
- Published
- 2017
- Full Text
- View/download PDF
49. Mutational Analysis of Recurrent Meningioma Progressing From Atypical to Rhabdoid Subtype.
- Author
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Bujko M, Machnicki MM, Grecka E, Rusetska N, Matyja E, Kober P, Mandat T, Rydzanicz M, Płoski R, Krajewski R, Bonicki W, Stokłosa T, and Siedlecki JA
- Subjects
- DNA-Binding Proteins, Female, Genetic Markers genetics, Genetic Predisposition to Disease genetics, Humans, Meningeal Neoplasms pathology, Meningioma pathology, Middle Aged, Mutation genetics, Neoplasm Recurrence, Local pathology, Rhabdoid Tumor genetics, Biomarkers, Tumor genetics, Meningeal Neoplasms genetics, Meningioma genetics, Neoplasm Recurrence, Local genetics, Nuclear Proteins genetics, Polymorphism, Single Nucleotide genetics, Transcription Factors genetics
- Abstract
Background: Rhabdoid meningioma is rare aggressive meningioma histological subtype that develops predominantly through progression from less malignant tumors. Owing to its low incidence, this tumor's biological background is unknown. The aim of this study was to profile somatic mutations in 4 meningioma samples from the same patient, derived previously from 4 subsequent tumor resections., Case Description: A 58-year-old woman presented with recurrent meningioma progressing from atypical to rhabdoid subtype. Four tumor samples that represent a primary tumor (atypical GII) and 3 recurrent tumors that were subsequently removed (anaplastic GIII, rhabdoid GIII, and anaplastic/rhabdoid GIII) from this patient were subjected to mutational analysis of coding sequences of 952 tumor-related genes. Three mutations were identified in all tumor samples exhibiting a high allelic frequency: ARID1A frameshift deletion, NF2 in-frame deletion, and missense variant of SRSF2. The predicted inactivating effect of ARID1A deletion was confirmed by immunohistochemical staining of tumor sections in which a high proportion of cells lacked protein expression. Additional low-allelic-fraction mutations were observed in all tumor samples, likely representing "passenger," low-effect mutations that reflect a clonal selection of tumor cells through malignant progression of the meningioma., Conclusion: The mutation of ARID1A that encodes the subunit of the SWI/SNF complex represents the most likely driver of the tumor's malignant potential. It also may be involved in the acquisition of the rhabdoid phenotype, given that mutations in chromatin remodeling proteins are the hallmark of atypical teratoid/rhabdoid tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
50. Validating candidate reference genes for qRT-PCR-based gene expression analysis in nonfunctioning pituitary adenomas.
- Author
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Bujko M, Rusetska N, and Mikula M
- Subjects
- Humans, Adenoma metabolism, Pituitary Neoplasms metabolism, Reverse Transcriptase Polymerase Chain Reaction methods
- Published
- 2016
- Full Text
- View/download PDF
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