19696
2018
eng
675
9
article
1
--
2018-12-18
--
Ras-Induced miR-146a and 193a Target Jmjd6 to Regulate Melanoma Progression
Ras genes are among the most commonly mutated genes in human cancer; yet our understanding of their oncogenic activity at the molecular mechanistic level is incomplete. To identify downstream events that mediate ras-induced cellular transformation in vivo, we analyzed global microRNA expression in three different models of Ras-induction and tumor formation in zebrafish. Six microRNAs were found increased in Ras-induced melanoma, glioma and in an inducible model of ubiquitous Ras expression. The upregulation of the microRNAs depended on the activation of the ERK and AKT pathways and to a lesser extent, on mTOR signaling. Two Ras-induced microRNAs (miR-146a and 193a) target Jmjd6, inducing downregulation of its mRNA and protein levels at the onset of Ras expression during melanoma development. However, at later stages of melanoma progression, jmjd6 levels were found elevated. The dynamic of Jmjd6 levels during progression of melanoma in the zebrafish model suggests that upregulation of the microRNAs targeting Jmjd6 may be part of an anti-cancer response. Indeed, triple transgenic fish engineered to express a microRNA-resistant Jmjd6 from the onset of melanoma have increased tumor burden, higher infiltration of leukocytes and shorter melanoma-free survival. Increased JMJD6 expression is found in several human cancers, including melanoma, suggesting that the up-regulation of Jmjd6 is a critical event in tumor progression.
The following link has been created to allow review of record GSE37015: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jjcrbiuicyyqgpc&acc=GSE37015.
Frontiers in Genetics
1664-8021
10.3389/fgene.2018.00675
urn:nbn:de:bvb:20-opus-196963
Frontiers in Genetics (2018) 9:675. doi: 10.3389/fgene.2018.00675
667787
037220
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Viviana Anelli
Anita Ordas
Susanne Kneitz
Leonel Munoz Sagredo
Victor Gourain
Manfred Schartl
Annemarie H. Meijer
Marina Mione
eng
uncontrolled
zebrafish
eng
uncontrolled
cancer models
eng
uncontrolled
microRNA
eng
uncontrolled
Jmjd6
eng
uncontrolled
ras
eng
uncontrolled
melanoma
eng
uncontrolled
miR-146a
eng
uncontrolled
miR-193a
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
OpenAIRE
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/19696/fgene-09-00675.pdf
17726
2018
eng
71
7
article
1
2019-02-25
--
--
BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1
Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-induced senescence-like state. Here, we show in several melanoma cell lines that BRAF inhibition induces a secretome with stimulating effect on fibroblasts and naive melanoma cells. Several senescence-associated factors were found to be transcribed and secreted in response to BRAF or MEK inhibition, among them members of the fibroblast growth factor family. We identified the growth factor FGF1 as mediator of resilience towards BRAF inhibition, which limits the pro-apoptotic effects of the drug and activates fibroblasts to secrete HGF. FGF1 regulation was mediated by the PI3K pathway and by FRA1, a direct target gene of the MAPK pathway. When FGFR inhibitors were applied in parallel to BRAF inhibitors, resilience was broken, thus providing a rationale for combined therapeutical application.
Oncogenesis
10.1038/s41389-018-0082-2
urn:nbn:de:bvb:20-opus-177261
Oncogenesis (2018) 7:71. DOI: 10.1038/s41389-018-0082-2
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Johannes Grimm
Anita Hufnagel
Marion Wobser
Andreas Borst
Sebastian Haferkamp
Roland Houben
Svenja Meierjohann
eng
uncontrolled
melanoma
eng
uncontrolled
senescence
eng
uncontrolled
BRAF
eng
uncontrolled
tumor
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
Förderzeitraum 2018
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17726/Grimm_Oncogenesis.pdf
12064
2014
eng
5040-53
13
5
article
1
2015-10-21
--
--
The MAPK pathway as an apoptosis enhancer in melanoma
Inhibition of RAF/MEK/ERK signaling is beneficial for many patients with BRAFV600E–mutated melanoma. However, primary and secondary resistances restrict long-lasting therapy success. Combination therapies are therefore urgently needed. Here, we evaluate the cellular effect of combining a MEK inhibitor with a genotoxic apoptosis inducer. Strikingly, we observed that an activated MAPK pathway promotes in several melanoma cell lines the pro-apoptotic response to genotoxic stress, and MEK inhibition reduces intrinsic apoptosis. This goes along with MEK inhibitor induced increased RAS and P-AKT levels. The protective effect of the MEK inhibitor depends on PI3K signaling, which prevents the induction of pro-apoptotic PUMA that mediates apoptosis after DNA damage. We could show that the MEK inhibitor dependent feedback loop is enabled by several factors, including EGF receptor and members of the SPRED family. The simultaneous knockdown of SPRED1 and SPRED2 mimicked the effects of MEK inhibitor such as PUMA repression and protection from apoptosis. Our data demonstrate that MEK inhibition of BRAFV600E-positive melanoma cells can protect from genotoxic stress, thereby achieving the opposite of the intended anti-tumorigenic effect of the combination of MEK inhibitor with inducers of intrinsic apoptosis.
Oncotarget
1949-2553
urn:nbn:de:bvb:20-opus-120649
Oncotarget, Vol. 5, No. 13, 5040-53
Johannes M. Haydn
Anita Hufnagel
Johannes Grimm
Katja Maurus
Manfred Schartl
Svenja Meierjohann
eng
uncontrolled
PI3K
eng
uncontrolled
melanoma
eng
uncontrolled
RAS
eng
uncontrolled
chemotherapy resistance
eng
uncontrolled
crosstalk
Pharmakologie, Therapeutik
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12064/110_Hydn_Oncotarget.pdf
26061
2021
eng
10
16
article
1
2022-03-16
--
--
Differential expression of transposable elements in the medaka melanoma model
Malignant melanoma incidence is rising worldwide. Its treatment in an advanced state is difficult, and the prognosis of this severe disease is still very poor. One major source of these difficulties is the high rate of metastasis and increased genomic instability leading to a high mutation rate and the development of resistance against therapeutic approaches. Here we investigate as one source of genomic instability the contribution of activation of transposable elements (TEs) within the tumor. We used the well-established medaka melanoma model and RNA-sequencing to investigate the differential expression of TEs in wildtype and transgenic fish carrying melanoma. We constructed a medaka-specific TE sequence library and identified TE sequences that were specifically upregulated in tumors. Validation by qRT- PCR confirmed a specific upregulation of a LINE and an LTR element in malignant melanomas of transgenic fish.
PLoS One
10.1371/journal.pone.0251713
urn:nbn:de:bvb:20-opus-260615
publish
PLoS One (2021) 16:10, e0251713. https://doi.org/10.1371/journal.pone.0251713
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Frederik Helmprobst
Susanne Kneitz
Barbara Klotz
Magali Naville
Corentin Dechaud
Jean-Nicolas Volff
Manfred Schartl
eng
uncontrolled
melanoma
eng
uncontrolled
genomics
eng
uncontrolled
transposable elements
eng
uncontrolled
cancer genomics
eng
uncontrolled
malignant tumors
eng
uncontrolled
gene prediction
eng
uncontrolled
human genomics
eng
uncontrolled
retrotransposons
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2021
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/26061/journal.pone.0251713.pdf
14602
2016
eng
357
17
article
1
2017-03-22
--
--
Germ cell and tumor associated piRNAs in the medaka and \(Xiphophorus\) melanoma models
Background
A growing number of studies report an abnormal expression of Piwi-interacting RNAs (piRNAs) and the piRNA processing enzyme Piwi in many cancers. Whether this finding is an epiphenomenon of the chaotic molecular biology of the fast dividing, neoplastically transformed cells or is functionally relevant to tumorigenesisis is difficult to discern at present. To better understand the role of piRNAs in cancer development small laboratory fish models can make a valuable contribution. However, little is known about piRNAs in somatic and neoplastic tissues of fish.
Results
To identify piRNA clusters that might be involved in melanoma pathogenesis, we use several transgenic lines of medaka, and platyfish/swordtail hybrids, which develop various types of melanoma. In these tumors Piwi, is expressed at different levels, depending on tumor type. To quantify piRNA levels, whole piRNA populations of testes and melanomas of different histotypes were sequenced. Because no reference piRNA cluster set for medaka or Xiphophorus was yet available we developed a software pipeline to detect piRNA clusters in our samples and clusters were selected that were enriched in one or more samples. We found several loci to be overexpressed or down-regulated in different melanoma subtypes as compared to hyperpigmented skin. Furthermore, cluster analysis revealed a clear distinction between testes, low-grade and high-grade malignant melanoma in medaka.
Conclusions
Our data imply that dysregulation of piRNA expression may be associated with development of melanoma. Our results also reinforce the importance of fish as a suitable model system to study the role of piRNAs in tumorigenesis.
BMC Genomics
10.1186/s12864-016-2697-z
urn:nbn:de:bvb:20-opus-146028
BMC Genomics (2016) 17:357 DOI 10.1186/s12864-016-2697-z
Susanne Kneitz
Rasmi R. Mishra
Domitille Chalopin
John Postlethwait
Wesley C. Warren
Ronald B. Walther
Manfred Schartl
eng
uncontrolled
small RNA-sequencing
eng
uncontrolled
melanoma
eng
uncontrolled
piRNA
eng
uncontrolled
fish model
Menschliche Anatomie, Zytologie, Histologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2016
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14602/026_Kneitz_art_10.1186_s12864-016-2697-z.pdf
12558
2015
eng
120
5
article
1
2016-01-26
--
--
Hypoxia independent drivers of melanoma angiogenesis
Tumor angiogenesis is a process which is traditionally regarded as the tumor’s response to low nutrient supply occurring under hypoxic conditions. However, hypoxia is not a pre-requisite for angiogenesis. The fact that even single tumor cells or small tumor cell aggregates are capable of attracting blood vessels reveals the early metastatic capability of tumor cells. This review sheds light on the hypoxia-independent mechanisms of tumor angiogenesis in melanoma.
Frontiers in Oncology
10.3389/fonc.2015.00102
urn:nbn:de:bvb:20-opus-125586
Frontiers in Oncology 5:102. doi: 10.3389/fonc.2015.00102
Svenja Meierjohann
eng
uncontrolled
melanoma
eng
uncontrolled
angiogenesis
eng
uncontrolled
hypoxia-independent
eng
uncontrolled
reactive oxygen species
eng
uncontrolled
NF-κB
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2015
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12558/Meierjohann_fonc-05-00102.pdf
12683
2012
eng
3456-3461
5
29
article
1
2016-02-10
--
--
Association between HRAS rs12628 and rs112587690 polymorphisms with the risk of melanoma in the North American population
HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case–control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk (OR = 3.83, p = 0.003; OR = 11.3, p = 0.033, respectively), while rs112587690 P1P3 frequency resulted significantly higher in the control group (OR = 0.5, p = 0.017). These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690.
Medical Oncology
dx.doi.org/10.1007/s12032-012-0255-3
urn:nbn:de:bvb:20-opus-126834
Medical Oncology (2012) 29:3456–3461 DOI 10.1007/s12032-012-0255-3
Sara Tomei
Sharon Adams
Lorenzo Uccellini
Davide Bedognetti
Valeria De Giorgi
Narnygerel Erdenebileg
Maria Libera Ascierto
Jennifer Reinboth
Qiuzhen Liu
Generoso Bevilacqua
Ena Wang
Chiara Mazzanti
Francesco M. Marincola
eng
uncontrolled
HRAS
eng
uncontrolled
polymorphism
eng
uncontrolled
melanoma
eng
uncontrolled
rs12628
eng
uncontrolled
rs112587690
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
Lehrstuhl für Biochemie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12683/Tomei_Medical_Oncology.pdf
5364
1992
eng
article
1
2011-12-09
--
--
Xmrk receptor tyrosine kinase is activated in Xiphophorus malignant melanoma
Xmrk encodes a putative transmembrane glycoprotein of the tyrosine kinase family and is a melanoma-inducing gene in Xiphophorus. We attempted to investigate the biological function of the putative Xmrk receptor by characterizing its signalling properties. Since a potential Iigand for Xmrk has not yet been identified, it has been difficult to analyse the biochemical properlies and biological function of this cell surface protein. In an approach towards such analyses, the Xmrk extracellular domain was replaced by the closely related Iigand-binding domain sequences of the human epidennal growth factor receptor (HER) and the ligand-induced activity of the chimeric HER-Xmrk proteinwas examined. We show that the Xmrk protein is a functional receptor tyrosine kinase, is highly active in malignant melanoma and displays a constitutive autophosphorylation activity possibly due to an activating mutation in its extracellular or transmembrane domain. In the focus formation assay the HER-Xmrk chimera is a potent transfonning protein equivalent to other tyrosine kinase oncoproteins.
urn:nbn:de:bvb:20-opus-61699
6169
In: Embo Journal (1992) , 11, 4239-4246
Deutsches Urheberrecht
Joachim Wittbrodt
Reiner Lammers
Barbara Malitschek
Axel Ullrich
Manfred Schartl
deu
swd
Physiologische Chemie
eng
uncontrolled
chimeric RTKs
eng
uncontrolled
melanoma
eng
uncontrolled
RTK
eng
uncontrolled
Xiphophorus
Chemie und zugeordnete Wissenschaften
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/5364/Schartl20.pdf