20316
2020
eng
3
9
article
1
--
2020-03-02
--
miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro
Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort (n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition.
Journal of Clinical Medicine
2077-0383
10.3390/jcm9030670
urn:nbn:de:bvb:20-opus-203168
swordwue
2020-04-27T20:30:00+00:00
attachment; filename=deposit.zip
c9789e245bf905fb71c09c358e3b4ec8
Journal of Clinical Medicine 2020, 9(3), 670; https://doi.org/10.3390/jcm9030670
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Markus Krebs
Antonio Giovanni Solimando
Charis Kalogirou
André Marquardt
Torsten Frank
Ioannis Sokolakis
Georgios Hatzichristodoulou
Susanne Kneitz
Ralf Bargou
Hubert Kübler
Bastian Schilling
Martin Spahn
Burkhard Kneitz
eng
uncontrolled
microRNA-221
eng
uncontrolled
high-risk Prostate Cancer
eng
uncontrolled
angiogenesis
eng
uncontrolled
Sunitinib
eng
uncontrolled
Tyrosine kinase inhibition
Medizin und Gesundheit
open_access
Urologische Klinik und Poliklinik
Pathologisches Institut
Theodor-Boveri-Institut für Biowissenschaften
Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
Import
Förderzeitraum 2020
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/20316/jcm-09-00670-v2.pdf
13771
2012
eng
2012
article
1
2016-08-25
--
--
The Role of Adjuvant Hormonal Treatment after Surgery for Localized High-Risk Prostate Cancer: Results of a Matched Multiinstitutional Analysis
Introduction. To assess the role of adjuvant androgen deprivation therapy (ADT) in high-risk prostate cancer patients (PCa) after surgery. Materials and Methods. The analysis case matched 172 high-risk PCa patients with positive section margins or non-organ confined disease and negative lymph nodes to receive adjuvant ADT (group 1, n=86 ) or no adjuvant ADT (group 2, n=86). Results. Only 11.6% of the patients died, 2.3% PCa related. Estimated 5–10-year clinical progression-free survival was 96.9% (94.3%) for group 1 and 73.7% (67.0%) for group 2, respectively. Subgroup analysis identified men with T2/T3a tumors at low-risk and T3b margins positive disease at higher risk for progression. Conclusion. Patients with T2/T3a tumors are at low-risk for metastatic disease and cancer-related death and do not need adjuvant ADT. We identified men with T3b margin positive disease at highest risk for clinical progression. These patients benefit from immediate adjuvant ADT.
Advances in Urology
10.1155/2012/612707
urn:nbn:de:bvb:20-opus-137712
Advances in Urology Volume 2012 (2012), Article ID 612707, 6 pages. DOI: 10.1155/2012/612707
Maria Schubert
Steven Joniau
Paolo Gontero
Susanne Kneitz
Claus-Jürgen Scholz
Burkhard Kneitz
Alberto Briganti
R. Jeffery Karnes
Bertrand Tombal
Jochen Walz
Chao-Yu Hsu
Giansilvio Marchioro
Pia Bader
Chris Bangma
Detlef Frohneberg
Markus Graefen
Fritz Schröder
Paul van Cangh
Hein van Poppel
Martin Spahn
eng
uncontrolled
prostate cancer
eng
uncontrolled
adjuvant hormonal treatment
Chirurgie und verwandte medizinische Fachrichtungen
open_access
Urologische Klinik und Poliklinik
Förderzeitraum 2011
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13771/Schubert_Advances_Urology_612707.pdf
11363
2014
eng
article
1
2015-05-21
--
--
Impact of miR-21, miR-126 and miR-221 as Prognostic Factors of Clear Cell Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava
Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients.
10.1371/journal.pone.0109877
urn:nbn:de:bvb:20-opus-113633
PLoS ONE 9(10): e109877. doi:10.1371/journal.pone.0109877
Daniel Claudius Vergho
Susanne Kneitz
Charis Kalogirou
Maximilian Burger
Markus Krebs
Andreas Rosenwald
Martin Spahn
Andreas Löser
Arkadius Kocot
Hubertus Riedmiller
Burkhard Kneitz
eng
uncontrolled
forecasting
eng
uncontrolled
metastasis
eng
uncontrolled
renal cancer
eng
uncontrolled
renal cell carcinoma
eng
uncontrolled
kidneys
eng
uncontrolled
surgical oncology
eng
uncontrolled
surgical and invasive medical procedures
eng
uncontrolled
regression analysis
Medizin und Gesundheit
open_access
Urologische Klinik und Poliklinik
Pathologisches Institut
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2014
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11363/146_Vergho_PLoS.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
9682
2013
eng
article
1
--
--
--
Distinct microRNA Expression Profile in Prostate Cancer Patients with Early Clinical Failure and the Impact of let-7 as Prognostic Marker in High-Risk Prostate Cancer
Background
The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact.
Methodology and Principal Findings
We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples.
Conclusion
Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.
PLoS ONE
10.1371/journal.pone.0065064
urn:nbn:de:bvb:20-opus-96825
In: PLoS ONE (2013) 8: 6, doi:10.1371/journal.pone.0065064
Maria Schubert
Martin Spahn
Susanne Kneitz
Claus Jürgen Scholz
Steven Joniau
Philipp Stroebel
Hubertus Riedmiller
Burkhard Kneitz
eng
uncontrolled
biomarkers
eng
uncontrolled
gene expression
eng
uncontrolled
gene targeting
eng
uncontrolled
luciferase
eng
uncontrolled
MircoRNA
eng
uncontrolled
microarrays
eng
uncontrolled
oncogenes
eng
uncontrolled
prostate cancer
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/9682/Schubert_journal.pone.0065064.pdf
11006
2014
eng
article
1
2015-02-25
--
--
Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma
Background
Renal cell carcinoma (RCC) is marked by high mortality rate. To date, no robust risk stratification by clinical or molecular prognosticators of cancer-specific survival (CSS) has been established for early stages. Transcriptional profiling of small non-coding RNA gene products (miRNAs) seems promising for prognostic stratification. The expression of miR-21 and miR-126 was analysed in a large cohort of RCC patients; a combined risk score (CRS)-model was constructed based on expression levels of both miRNAs.
Methods
Expression of miR-21 and miR-126 was evaluated by qRT-PCR in tumour and adjacent non-neoplastic tissue in n = 139 clear cell RCC patients. Relation of miR-21 and miR-126 expression with various clinical parameters was assessed. Parameters were analysed by uni- and multivariate COX regression. A factor derived from the z-score resulting from the COX model was determined for both miRs separately and a combined risk score (CRS) was calculated multiplying the relative expression of miR-21 and miR-126 by this factor. The best fitting COX model was selected by relative goodness-of-fit with the Akaike information criterion (AIC).
Results
RCC with and without miR-21 up- and miR-126 downregulation differed significantly in synchronous metastatic status and CSS. Upregulation of miR-21 and downregulation of miR-126 were independently prognostic. A combined risk score (CRS) based on the expression of both miRs showed high sensitivity and specificity in predicting CSS and prediction was independent from any other clinico-pathological parameter. Association of CRS with CSS was successfully validated in a testing cohort containing patients with high and low risk for progressive disease.
Conclusions
A combined expression level of miR-21 and miR-126 accurately predicted CSS in two independent RCC cohorts and seems feasible for clinical application in assessing prognosis.
10.1186/1471-2407-14-25
urn:nbn:de:bvb:20-opus-110061
In: BMC Cancer 14:25 (2014). doi:10.1186/1471-2407-14-25
Daniel Vergho
Susanne Kneitz
Andreas Rosenwald
Charlotte Scherer
Martin Spahn
Maximilian Burger
Hubertus Riedmiller
Burkhard Kneitz
eng
uncontrolled
Renal cell carcinoma
eng
uncontrolled
RCC
eng
uncontrolled
Kidney cancer
eng
uncontrolled
miRNA
eng
uncontrolled
miR-21
eng
uncontrolled
miR-126
eng
uncontrolled
Prognosis
eng
uncontrolled
Profiling
eng
uncontrolled
Biomarker
eng
uncontrolled
Tumour markers
Medizin und Gesundheit
open_access
Urologische Klinik und Poliklinik
Pathologisches Institut
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2014
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11006/005_Vergho_BMCCancer.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