20584
2020
eng
5
9
article
1
--
2020-05-24
--
Anti-angiogenesis and immunotherapy: novel paradigms to envision tailored approaches in renal cell-carcinoma
Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintains and reinforces their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy.
Journal of Clinical Medicine
2077-0383
10.3390/jcm9051594
urn:nbn:de:bvb:20-opus-205846
swordwue
2020-06-10T16:00:21+00:00
attachment; filename=deposit.zip
21b9e55a4fc95fab17558a9134c72b2b
Journal of Clinical Medicine (2020) 9:5, 1594. https://doi.org/10.3390/jcm9051594
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Antonella Argentiero
Antonio Giovanni Solimando
Markus Krebs
Patrizia Leone
Nicola Susca
Oronzo Brunetti
Vito Racanelli
Angelo Vacca
Nicola Silvestris
eng
uncontrolled
renal cell carcinoma
eng
uncontrolled
angiogenesis
eng
uncontrolled
immune-checkpoint inhibitor
eng
uncontrolled
tumor microenvironment
eng
uncontrolled
molecular subtypes
eng
uncontrolled
prognostic-biomarkers
eng
uncontrolled
predictive factors
Medizin und Gesundheit
open_access
Urologische Klinik und Poliklinik
Import
Comprehensive Cancer Center Mainfranken
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/20584/jcm-09-01594.pdf
21930
2020
eng
11
8
article
1
--
2020-11-18
--
Detection Rate of \(^{68}\)Ga-PSMA Ligand PET/CT in Patients with Recurrent Prostate Cancer and Androgen Deprivation Therapy
Prostate-specific membrane antigen (PSMA) ligand PET/CT enables the localization of tumor lesions in patients with recurrent prostate cancer, but it is unclear whether androgen deprivation therapy (ADT) influences diagnostic accuracy. The aim of this study was to evaluate the effect of ADT on the detection rate of \(^{68}\)Ga-PSMA ligand PET/CT. Thus, 399 patients with initial radical prostatectomy and 68Ga-PSMA ligand PET/CT during PSA relapse were retrospectively evaluated. Propensity score matching was used to create two balanced groups of 62 subjects who either did or did not receive ADT within six months before imaging. All \(^{68}\)Ga-PSMA ligand PET/CT were evaluated visually and with semiquantitative measures. The detection rate of tumor recurrence was significantly higher in the group with ADT (88.7% vs. 72.6%, p = 0.02) and improved with increasing PSA-levels in both groups. In subjects with pathological PET/CT and ADT, whole-body total lesion PSMA (p < 0.01) and PSMA-derived tumor volume (p < 0.01) were significantly higher than in those without ADT. More PSMA-positive lesions and higher PSMA-derived volumetric parameters in patients with ADT suggest that a better detection rate is related to a (biologically) more advanced disease stage. Due to high detection rates in patients with PSA-levels < 2 ng/mL, the withdrawal of ADT before PSMA ligand PET/CT cannot be recommended.
Biomedicines
2227-9059
10.3390/biomedicines8110511
urn:nbn:de:bvb:20-opus-219301
2020-12-18T15:31:44+00:00
sword
swordwue
attachment; filename=deposit.zip
7fe32655cddbdb295a686265bdce0c29
Biomedicines 2020, 8(11), 511; https://doi.org/10.3390/biomedicines8110511
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Joachim Brumberg
Melanie Beckl
Alexander Dierks
Andreas Schirbel
Markus Krebs
Andreas Buck
Hubert Kübler
Constantin Lapa
Anna Katharina Seitz
eng
uncontrolled
68Ga-PSMA ligand PET/CT
eng
uncontrolled
androgen deprivation therapy
eng
uncontrolled
detection rate
eng
uncontrolled
recurrent prostate cancer
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Urologische Klinik und Poliklinik
Import
Förderzeitraum 2020
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/21930/biomedicines-08-00511.pdf
27181
2022
eng
484-490
3
25
article
1
--
--
--
High expression of Sterol-O-Acyl transferase 1 (SOAT1), an enzyme involved in cholesterol metabolism, is associated with earlier biochemical recurrence in high risk prostate cancer
Background
Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans.
Objective
To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa.
Patients and Methods
Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards modeling were used to compare outcome.
Main Outcome Measure
Biochemical recurrence (BCR) free survival.
Results
SOAT1 expression was high in 73 (25%) and low in 219 (75%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14%) and at low levels in 249 (86%) samples (not evaluable: 16). By Kaplan-Meier analysis, we found significantly shorter median BCR free survival of 93 months (95% confidence interval 23.6-123.1) in patients with high SOAT1 vs. 134 months (112.6-220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95% CI 1.57-3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression CONCLUSIONS: SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target.
Prostate Cancer and Prostatic Diseases
1476-5608
10.1038/s41391-021-00431-3
34326474
urn:nbn:de:bvb:20-opus-271819
publish
Prostate Cancer and Prostatic Diseases 2022, 25(3):484-490. DOI: 10.1038/s41391-021-00431-3
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Carolin Eckhardt
Iuliu Sbiera
Markus Krebs
Silviu Sbiera
Martin Spahn
Burkhard Kneitz
Steven Joniau
Martin Fassnacht
Hubert Kübler
Isabel Weigand
Matthias Kroiss
eng
uncontrolled
prostate cancer
eng
uncontrolled
SOAT1
eng
uncontrolled
cholesterol metabolism
Medizin und Gesundheit
open_access
Urologische Klinik und Poliklinik
Medizinische Klinik und Poliklinik I
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/27181/Eckhardt_Prostate.pdf
20589
2020
eng
5
9
article
1
--
2020-05-08
--
Metabolic Tumour Volume from PSMA PET/CT Scans of Prostate Cancer Patients during Chemotherapy — Do Different Software Solutions Deliver Comparable Results?
(1) Background: Prostate-specific membrane antigen (PSMA)-derived tumour volume (PSMA-TV) and total lesion PSMA (TL-PSMA) from PSMA PET/CT scans are promising biomarkers for assessing treatment response in prostate cancer (PCa). Currently, it is unclear whether different software tools for assessing PSMA-TV and TL-PSMA produce comparable results. (2) Methods: \(^{68}\)Ga-PSMA PET/CT scans from n = 21 patients with castration-resistant PCa (CRPC) receiving chemotherapy were identified from our single-centre database. PSMA-TV and TL-PSMA were calculated with Syngo.via (Siemens) as well as the freely available Beth Israel plugin for FIJI (Fiji Is Just ImageJ) before and after chemotherapy. While statistical comparability was illustrated and quantified via Bland-Altman diagrams, the clinical agreement was estimated by matching PSMA-TV, TL-PSMA and relative changes of both variables during chemotherapy with changes in serum PSA (ΔPSA) and PERCIST (Positron Emission Response Criteria in Solid Tumors). (3) Results: Comparing absolute PSMA-TV and TL-PSMA as well as Bland–Altman plotting revealed a good statistical comparability of both software algorithms. For clinical agreement, classifying therapy response did not differ between PSMA-TV and TL-PSMA for both software solutions and showed highly positive correlations with BR. (4) Conclusions: due to the high levels of statistical and clinical agreement in our CRPC patient cohort undergoing taxane chemotherapy, comparing PSMA-TV and TL-PSMA determined by Syngo.via and FIJI appears feasible.
Journal of Clinical Medicine
2077-0383
10.3390/jcm9051390
urn:nbn:de:bvb:20-opus-205893
swordwue
2020-06-11T06:08:01+00:00
attachment; filename=deposit.zip
6fdf610833cc12829a927166e2d90567
Journal of Clinical Medicine 2020, 9(5), 1390; https://doi.org/10.3390/jcm9051390
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Philipp E. Hartrampf
Marieke Heinrich
Anna Katharina Seitz
Joachim Brumberg
Ioannis Sokolakis
Charis Kalogirou
Andreas Schirbel
Hubert Kübler
Andreas K. Buck
Constantin Lapa
Markus Krebs
eng
uncontrolled
prostate-specific membrane antigen (PSMA)
eng
uncontrolled
metabolic tumour volume (MTV)
eng
uncontrolled
total lesion PSMA
eng
uncontrolled
biomarker
eng
uncontrolled
software
eng
uncontrolled
comparability
eng
uncontrolled
agreement
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Urologische Klinik und Poliklinik
Import
Förderzeitraum 2020
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/20589/jcm-09-01390-v2.pdf
27119
2022
eng
5
11
article
1
--
2022-04-26
--
Reduced segmentation of lesions is comparable to whole-body segmentation for response assessment by PSMA PET/CT: initial experience with the keyhole approach
Simple Summary
The calculation of PSMA-positive tumor volume (PSMA-TV) of the whole body from PSMA PET scans for response evaluation remains a time-consuming procedure. We hypothesized that it may be possible to quantify changes in PSMA-TV by considering only a limited number of representative tumor lesions. Changes in the whole-body PSMA-TV of 65 patients were comparable to the changes in PSMA-TV after including only the ten largest lesions. Moreover, changes in PSMA-TV correlated well with changes in PSA levels, as did the changes in PSMA-TV with the reduced number of lesions. We conclude that a response assessment using PSMA-TV with a reduced number of lesions is feasible and could lead to a simplified process for evaluating PSMA PET/CT.
Abstract
(1) Background: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-derived parameters, such as the commonly used standardized uptake value (SUV) and PSMA-positive tumor volume (PSMA-TV), have been proposed for response assessment in metastatic prostate cancer (PCa) patients. However, the calculation of whole-body PSMA-TV remains a time-consuming procedure. We hypothesized that it may be possible to quantify changes in PSMA-TV by considering only a limited number of representative lesions. (2) Methods: Sixty-five patients classified into different disease stages were assessed by PSMA PET/CT for staging and restaging after therapy. Whole-body PSMA-TV and whole-body SUV\(_{max}\) were calculated. We then repeated this calculation only including the five or ten hottest or largest lesions. The corresponding serum levels of prostate-specific antigen (PSA) were also determined. The derived delta between baseline and follow-up values provided the following parameters: ΔSUV\(_{maxall}\), ΔSUV\(_{max10}\), ΔSUV\(_{max5}\), ΔPSMA-TV\(_{all}\), ΔPSMA-TV\(_{10}\), ΔPSMA-TV\(_{5}\), ΔPSA. Finally, we compared the findings from our whole-body segmentation with the results from our keyhole approach (focusing on a limited number of lesions) and correlated all values with the biochemical response (ΔPSA). (3) Results: Among patients with metastatic hormone-sensitive PCa (mHSPC), none showed a relevant deviation for ΔSUV\(_{max10}\)/ΔSUV\(_{max5}\) or ΔPSMA-TV\(_{10}\)/ΔPSMA-TV\(_{5}\) compared to ΔSUV\(_{maxall}\) and ΔPSMA-TV\(_{all}\). For patients treated with taxanes, up to 6/21 (28.6%) showed clinically relevant deviations between ΔSUV\(_{maxall}\) and ΔSUV\(_{max10}\) or ΔSUV\(_{max5}\), but only up to 2/21 (9.5%) patients showed clinically relevant deviations between ΔPSMA-TV\(_{all}\) and ΔPSMA-TV\(_{10}\) or ΔPSMA-TV\(_{5}\). For patients treated with radioligand therapy (RLT), up to 5/28 (17.9%) showed clinically relevant deviations between ΔSUV\(_{maxall}\) and ΔSUV\(_{max10}\) or ΔSUV\(_{max5}\), but only 1/28 (3.6%) patients showed clinically relevant deviations between ΔPSMA-TV\(_{all}\) and ΔPSMA-TV\(_{10}\) or ΔPSMA-TV\(_{5}\). The highest correlations with ΔPSA were found for ΔPSMA-TV\(_{all}\) (r ≥ 0.59, p ≤ 0.01), followed by ΔPSMA-TV\(_{10}\) (r ≥ 0.57, p ≤ 0.01) and ΔPSMA-TV\(_{5}\) (r ≥ 0.53, p ≤ 0.02) in all cohorts. ΔPSA only correlated with ΔSUV\(_{maxall}\) (r = 0.60, p = 0.02) and with ΔSUV\(_{max10}\) (r = 0.53, p = 0.03) in the mHSPC cohort, as well as with ΔSUV\(_{maxall}\) (r = 0.51, p = 0.01) in the RLT cohort. (4) Conclusion: Response assessment using PSMA-TV with a reduced number of lesions is feasible, and may allow for a simplified evaluation process for PSMA PET/CT.
Biology
2079-7737
10.3390/biology11050660
urn:nbn:de:bvb:20-opus-271191
2022-05-09T06:54:08+00:00
sword
swordwue
attachment; filename=deposit.zip
99dad9b133f83c43d656ed4558e39a73
Biology (2022) 11:5, 660. doi:10.3390/biology11050660
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Philipp E. Hartrampf
Markus Krebs
Lea Peter
Marieke Heinrich
Julia Ruffing
Charis Kalogirou
Maximilian Weinke
Joachim Brumberg
Hubert Kübler
Andreas K. Buck
Rudolf A. Werner
Anna Katharina Seitz
eng
uncontrolled
PET/CT
eng
uncontrolled
PSMA-TV
eng
uncontrolled
SUV
eng
uncontrolled
prostate cancer
eng
uncontrolled
taxane
eng
uncontrolled
radioligand therapy
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Urologische Klinik und Poliklinik
Import
Comprehensive Cancer Center Mainfranken
Förderzeitraum 2022
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/27119/biology-11-00660.pdf
32576
2019
eng
19
article
1
2023-08-18
--
--
miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo
Background
Despite latest advances in prostate cancer (PCa) therapy, PCa remains the third-leading cause of cancer-related death in European men. Dysregulation of microRNAs (miRNAs), small non-coding RNA molecules with gene expression regulatory function, has been reported in all types of epithelial and haematological cancers. In particular, miR-221-5p alterations have been reported in PCa.
Methods
miRNA expression data was retrieved from a comprehensive publicly available dataset of 218 PCa patients (GSE21036) and miR-221-5p expression levels were analysed. The functional role of miR-221-5p was characterised in androgen- dependent and androgen- independent PCa cell line models (C4–2 and PC-3M-Pro4 cells) by miR-221-5p overexpression and knock-down experiments. The metastatic potential of highly aggressive PC-3M-Pro4 cells overexpressing miR-221-5p was determined by studying extravasation in a zebrafish model. Finally, the effect of miR-221-5p overexpression on the growth of PC-3M-Pro4luc2 cells in vivo was studied by orthotopic implantation in male Balb/cByJ nude mice and assessment of tumor growth.
Results
Analysis of microRNA expression dataset for human primary and metastatic PCa samples and control normal adjacent benign prostate revealed miR-221-5p to be significantly downregulated in PCa compared to normal prostate tissue and in metastasis compared to primary PCa. Our in vitro data suggest that miR-221-5p overexpression reduced PCa cell proliferation and colony formation. Furthermore, miR-221-5p overexpression dramatically reduced migration of PCa cells, which was associated with differential expression of selected EMT markers. The functional changes of miR-221-5p overexpression were reversible by the loss of miR-221-5p levels, indicating that the tumor suppressive effects were specific to miR-221-5p. Additionally, miR-221-5p overexpression significantly reduced PC-3M-Pro4 cell extravasation and metastasis formation in a zebrafish model and decreased tumor burden in an orthotopic mouse model of PCa.
Conclusions
Together these data strongly support a tumor suppressive role of miR-221-5p in the context of PCa and its potential as therapeutic target.
BMC Cancer
10.1186/s12885-019-5819-6
urn:nbn:de:bvb:20-opus-325762
publish
BMC Cancer (2019) 19:627. https://doi.org/10.1186/s12885-019-5819-6
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Mirjam Kiener
Lanpeng Chen
Markus Krebs
Joȅl Grosjean
Irena Klima
Charis Kalogirou
Hubertus Riedmiller
Burkhard Kneitz
George N. Thalmann
Ewa Snaar-Jagalska
Martin Spahn
Marianna Kruithof-de Julio
Eugenio Zoni
eng
uncontrolled
prostate cancer
eng
uncontrolled
miR-221-5p
eng
uncontrolled
proliferation
eng
uncontrolled
migration
eng
uncontrolled
tumor suppressor miRNA
Medizin und Gesundheit
open_access
Urologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/32576/s12885-019-5819-6.pdf
9732
2013
eng
article
1
--
--
--
MiR-205 Is Progressively Down-Regulated in Lymph Node Metastasis but Fails as a Prognostic Biomarker in High-Risk Prostate Cancer
The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the prognostic potential of miR-205 in HRPCa study and validation cohorts, setting defined clinical endpoints for both. We demonstrate miR-205 to be significantly down-regulated in over 70% of the HRPCa samples analysed and that reconstitution of miR-205 causes inhibition of proliferation and invasiveness in prostate cancer (PCa) cell lines. Additionally, miR-205 is increasingly down-regulated in lymph node metastases compared to the primary tumour indicating that miR-205 plays a role in migration of PCa cells from the original location into extraprostatic tissue. Nevertheless, down-regulation of miR-205 in primary PCa was not correlated to the synchronous presence of metastasis and failed to predict the outcome for HRPCa patients. Moreover, we found a tendency for miR-205 up-regulation to correlate with an adverse outcome of PCa patients suggesting a pivotal role of miR-205 in tumourigenesis. Overall, we showed that miR-205 is involved in the development and metastasis of PCa, but failed to work as a useful clinical biomarker in HRPCa. These findings might have implications for the use of miR-205 as a prognostic or therapeutic target in HRPCa.
International Journal of Molecular Sciences
10.3390/ijms141121414
urn:nbn:de:bvb:20-opus-97321
Microarray Core Unit, Interdisciplinary Center for Clinical Science, University of Würzburg, Versbacher Straße, Würzburg 97080, Germany
In: International Journal of Molecular Sciences (2013) 14: 11, 21414-34, doi:10.3390/ijms141121414
Burkhard Kneitz
Charis Kalogirou
Martin Spahn
Markus Krebs
Steven Joniau
Evelyne Lerut
Maximilian Burger
Claus-Jürgen Scholz
Susanne Kneitz
Hubertus Riedmiller
eng
uncontrolled
high-risk prostate cancer
eng
uncontrolled
microRNA
eng
uncontrolled
miR-205
eng
uncontrolled
prognosis
eng
uncontrolled
biomarker
Medizin und Gesundheit
open_access
Urologische Klinik und Poliklinik
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2013
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/9732/Kneitz_ijms141121414.pdf
31104
2023
eng
7
15
article
1
--
2023-03-26
--
Critical evaluation of a microRNA-based risk classifier predicting cancer-specific survival in renal cell carcinoma with tumor thrombus of the inferior vena cava
(1) Background: Clear cell renal cell carcinoma extending into the inferior vena cava (ccRCC\(^{IVC}\)) represents a clinical high-risk setting. However, there is substantial heterogeneity within this patient subgroup regarding survival outcomes. Previously, members of our group developed a microRNA(miR)-based risk classifier — containing miR-21-5p, miR-126-3p and miR-221-3p expression — which significantly predicted the cancer-specific survival (CSS) of ccRCC\(^{IVC}\) patients. (2) Methods: Examining a single-center cohort of tumor tissue from n = 56 patients with ccRCC\(^{IVC}\), we measured the expression levels of miR-21, miR-126, and miR-221 using qRT-PCR. The prognostic impact of clinicopathological parameters and miR expression were investigated via single-variable and multivariable Cox regression. Referring to the previously established risk classifier, we performed Kaplan–Meier analyses for single miR expression levels and the combined risk classifier. Cut-off values and weights within the risk classifier were taken from the previous study. (3) Results: miR-21 and miR-126 expression were significantly associated with lymphonodal status at the time of surgery, the development of metastasis during follow-up, and cancer-related death. In Kaplan–Meier analyses, miR-21 and miR-126 significantly impacted CSS in our cohort. Moreover, applying the miR-based risk classifier significantly stratified ccRCC\(^{IVC}\) according to CSS. (4) Conclusions: In our retrospective analysis, we successfully validated the miR-based risk classifier within an independent ccRCC\(^{IVC}\) cohort.
Cancers
2072-6694
10.3390/cancers15071981
urn:nbn:de:bvb:20-opus-311040
2023-04-05T11:29:20+00:00
sword
swordwue
attachment; filename=deposit.zip
b351331f3c968c616c904513dc897dd1
Cancers (2023) 15:7, 1981. https://doi.org/10.3390/cancers15071981
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Mischa J. Kotlyar
Markus Krebs
Antonio Giovanni Solimando
André Marquardt
Maximilian Burger
Hubert Kübler
Ralf Bargou
Susanne Kneitz
Wolfgang Otto
Johannes Breyer
Daniel C. Vergho
Burkhard Kneitz
Charis Kalogirou
eng
uncontrolled
kidney cancer
eng
uncontrolled
RCC
eng
uncontrolled
venous infiltration
eng
uncontrolled
biomarker
eng
uncontrolled
miR
eng
uncontrolled
risk stratification
Medizin und Gesundheit
open_access
Urologische Klinik und Poliklinik
Theodor-Boveri-Institut für Biowissenschaften
Import
Comprehensive Cancer Center Mainfranken
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/31104/cancers-15-01981.pdf
20248
2019
eng
6392748
2019
article
1
2020-04-01
--
--
miR-221 Augments TRAIL-mediated apoptosis in prostate cancer cells by inducing endogenous TRAIL expression and targeting the functional repressors SOCS3 and PIK3R1
miR-221 is regarded as an oncogene in many malignancies, and miR-221-mediated resistance towards TRAIL was one of the first oncogenic roles shown for this small noncoding RNA. In contrast, miR-221 is downregulated in prostate cancer (PCa), thereby implying a tumour suppressive function. By using proliferation and apoptosis assays, we show a novel feature of miR-221 in PCa cells: instead of inducing TRAIL resistance, miR-221 sensitized cells towards TRAIL-induced proliferation inhibition and apoptosis induction. Partially responsible for this effect was the interferon-mediated gene signature, which among other things contained an endogenous overexpression of the TRAIL encoding gene TNFSF10. This TRAIL-friendly environment was provoked by downregulation of the established miR-221 target gene SOCS3. Moreover, we introduced PIK3R1 as a target gene of miR-221 in PCa cells. Proliferation assays showed that siRNA-mediated downregulation of SOCS3 and PIK3R1 mimicked the effect of miR-221 on TRAIL sensitivity. Finally, Western blotting experiments confirmed lower amounts of phospho-Akt after siRNA-mediated downregulation of PIK3R1 in PC3 cells. Our results further support the tumour suppressing role of miR-221 in PCa, since it sensitises PCa cells towards TRAIL by regulating the expression of the oncogenes SOCS3 and PIK3R1. Given the TRAIL-inhibiting effect of miR-221 in various cancer entities, our results suggest that the influence of miR-221 on TRAIL-mediated apoptosis is highly context- and entity-dependent.
BioMed Research International
10.1155/2019/6392748
urn:nbn:de:bvb:20-opus-202480
BioMed Research International (2019) 2019:6392748. https://doi.org/10.1155/2019/6392748
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Markus Krebs
Christoph Behrmann
Charis Kalogirou
Ioannis Sokolakis
Susanne Kneitz
Marianna Kruithof-de Julio
Eugenio Zoni
Anne Rech
Bastian Schilling
Hubert Kübler
Martin Spahn
Burkhard Kneitz
eng
uncontrolled
Cancer Cell
Biowissenschaften; Biologie
Medizin und Gesundheit
open_access
Urologische Klinik und Poliklinik
Theodor-Boveri-Institut für Biowissenschaften
Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
Förderzeitraum 2019
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/20248/Krebs_BioMedResearchInternational_2019.pdf
13764
2016
deu
doctoralthesis
1
2016-08-22
--
2016-06-15
microRNA-221 und ihr Einfluss auf Zytokin-vermittelte Signalwege im Hochrisiko-Karzinom der Prostata
microRNA-221 and its influence on cytokine-mediated signaling pathways in high-risk prostate cancer
Der klinische Verlauf von Prostatakarzinom(PCa)-Erkrankungen ist extrem unterschiedlich und lässt sich mit den bisher üblichen Verfahren wie der feingeweblichen Beurteilung der Prostatastanzbiopsie bzw. des OP-Präparates und der PSA-Wert-Bestimmung nur unzureichend vorhersagen. Für eine bessere Versorgung von PCa-Patienten sind deshalb neuartige Marker notwendig, die das individuelle Progressions-Risiko bestimmen. Ein hoffnungsvoller Ansatz sind miRNA-Vertreter als Prognose-Parameter. Besonders interessant in dieser Hinsicht ist miR-221, die im PCa-Gewebe signifikant niedriger exprimiert wird. Jedoch existieren für diese in den meisten Neoplasien als Onkogen betrachtete miRNA kaum Erklärungsansätze für eine tumorsuppressive Funktion im PCa.
Die vorliegende Arbeit konnte mit Hilfe von Microarray-basierten Expressionsanalysen und deren bioinformatischer Auswertung sowie zell- und molekularbiologischen Experimenten erstmals zeigen, dass miR-221 das protektive Interferon-Signal in PCa-Zellen stärkt und auf diese Weise deren Proliferation hemmt. Daneben konnten zwei prominente Inhibitoren dieses Signals, IRF2 und SOCS3, als neue Zielgene von miR-221 in vitro nachgewiesen und eine Korrelation von miR-221 mit diesen Zielgenen auch in PCa-Nativmaterial identifiziert werden. Somit konnte erstmals ein Mechanismus der – vorher lediglich aufgrund der Herabregulation in PCa-Nativmaterial postulierten – tumorsuppressiven Funktion von miR-221 im Rahmen der PCa-Entstehung und -Progression dargestellt werden.
Eine Aktivierung des JAK / STAT-vermittelten Interferon-Signals durch miR-221 erscheint auch in einem breiteren infektiologischen Kontext interessant – sind doch zahlreiche Virenarten wie das HI-Virus, Hepatitis- und Herpesviren in der Lage, die zelluläre miR-221-Expression zu vermindern und auf diese Weise wohl das antivirale Interferon-Signal zu umgehen. Die Erhöhung der zellulären miR-221-Spiegel könnte nach diesem Prinzip auch Interferon-basierte Therapie-Strategien unterstützen bzw. erst ermöglichen.
Für das PCa müssen weitere experimentelle sowie klinisch-translationale Untersuchungen zeigen, ob miR-221 als Bestandteil einer Biomarker-Signatur dazu beiträgt, Patienten mit einem letalen PCa frühzeitig zu identifizieren und der dringend notwendigen Primärtherapie bzw. einer adjuvanten Behandlung zuzuführen. Im Gegenzug könnte zahlreichen Patienten, deren (hohe) miR-221-Expression im Tumorgewebe einen günstigeren Verlauf prognostiziert, die übermäßige Therapie erspart werden.
The clinical course of prostate cancer (PCa) is extremely heterogeneous and cannot be predicted sufficiently with usual procedures such as histological examination of prostate biopsies and surgical specimen or determination of PSA values. For a better treatment of PCa patients, novel markers are necessary which predict individual progression risk. MicroRNAs are promising biomarker candidates and miR-221 – which is significantly downregulated in prostate cancer tissue – seems especially interesting. However, as this specific microRNA plays an oncogenic role in various malignancies, no potential tumor suppressive functions are known.
By using Microarray-based gene expression analysis, bioinformatical algorithms, cell culture and molecular biology techniques, this thesis could show that miR-221 strengthens interferon signaling in PCa cells thereby serving as a tumor suppressor. Moreover, two prominent inhibitors of this signal, IRF2 and SOCS3, were introduced as new miR-221 target genes in vitro and a negative correlation of these targets and miR-221 was shown for PCa specimen. Altogether, this is the first miR-221-mediated mechanism fitting in with the previously postulated tumor suppressor role of miR-221 in PCa.
An activation of JAK / STAT-mediated interferon signaling by miR-221 also seems interesting from an infectious diseases perspective. Several viruses like HIV and members of the Hepatitis and Herpes family are able to lower the cellular miR-221 expression, thereby possibly weakening the antiviral interferon signal.
For PCa, further experimental as well as clinical-translational approaches have to determine whether miR-221 could be a part of a clinically relevant biomarker signature. This could help to identify and subsequently treat patients with a high-risk PCa, whereas many patients – with a prognostically favorable high miR-221 expression in tumor tissue – could be spared an overtreatment.
urn:nbn:de:bvb:20-opus-137644
X 126741
Markus Karl Ludwig Krebs
deu
swd
miRNS
deu
swd
Prostatakrebs
deu
swd
Interferon
mul
uncontrolled
microRNA-221
deu
uncontrolled
Interferonsignal
mul
uncontrolled
Biomarker
deu
uncontrolled
Hochrisikokarzinom der Prostata
Menschliche Anatomie, Zytologie, Histologie
open_access
Urologische Klinik und Poliklinik
Universität Würzburg
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13764/Krebs_Markus_miR-221.pdf