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  1. Article: Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy.

    Montagnani, Valentina / Stecca, Barbara

    Cancers

    2019  Volume 11, Issue 4

    Abstract: Hedgehog (HH) signaling is an evolutionarily conserved pathway that is crucial for growth and tissue patterning during embryonic development. It is mostly quiescent in the adult, where it regulates tissue homeostasis and stem cell behavior. Aberrant ... ...

    Abstract Hedgehog (HH) signaling is an evolutionarily conserved pathway that is crucial for growth and tissue patterning during embryonic development. It is mostly quiescent in the adult, where it regulates tissue homeostasis and stem cell behavior. Aberrant reactivation of HH signaling has been associated to several types of cancer, including those in the skin, brain, prostate, breast and hematological malignancies. Activation of the canonical HH signaling is triggered by binding of HH ligand to the twelve-transmembrane protein PATCHED. The binding releases the inhibition of the seven-transmembrane protein SMOOTHENED (SMO), leading to its phosphorylation and activation. Hence, SMO activates the transcriptional effectors of the HH signaling, that belong to the GLI family of transcription factors, acting through a not completely elucidated intracellular signaling cascade. Work from the last few years has shown that protein kinases phosphorylate several core components of the HH signaling, including SMO and the three GLI proteins, acting as powerful regulatory mechanisms to fine tune HH signaling activities. In this review, we will focus on the mechanistic influence of protein kinases on HH signaling transduction. We will also discuss the functional consequences of this regulation and the possible implications for cancer therapy.
    Language English
    Publishing date 2019-03-29
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers11040449
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: E3 ubiquitin ligase PARK2, an inhibitor of melanoma cell growth, is repressed by the oncogenic ERK1/2-ELK1 transcriptional axis.

    Montagnani, Valentina / Maresca, Luisa / Apollo, Alessandro / Pepe, Sara / Carr, Ryan M / Fernandez-Zapico, Martin E / Stecca, Barbara

    The Journal of biological chemistry

    2020  Volume 295, Issue 47, Page(s) 16058–16071

    Abstract: Malignant melanoma, the most aggressive form of skin cancer, is characterized by high prevalence ... ...

    Abstract Malignant melanoma, the most aggressive form of skin cancer, is characterized by high prevalence of
    MeSH term(s) Amino Acid Substitution ; Cell Line, Tumor ; GTP Phosphohydrolases/genetics ; GTP Phosphohydrolases/metabolism ; HEK293 Cells ; Humans ; MAP Kinase Signaling System ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mutation, Missense ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; ets-Domain Protein Elk-1/genetics ; ets-Domain Protein Elk-1/metabolism
    Chemical Substances ELK1 protein, human ; Membrane Proteins ; ets-Domain Protein Elk-1 ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; parkin protein (EC 2.3.2.27) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; NRAS protein, human (EC 3.6.1.-)
    Language English
    Publishing date 2020-09-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA120.014615
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.108: Show issues Location:
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  3. Article ; Online: Exome sequencing in primary melanoma identifies novel drivers of melanoma progression.

    Montagnani, Valentina / Benelli, Matteo / Apollo, Alessandro / Pandolfi, Silvia / Gerlini, Gianni / Borgognoni, Lorenzo / Stecca, Barbara

    Journal of translational medicine

    2015  Volume 13, Page(s) 2070

    Language English
    Publishing date 2015
    Publishing country England
    Document type Journal Article
    ISSN 1479-5876
    ISSN (online) 1479-5876
    DOI 10.1186/1479-5876-13-S1-P2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Tumor-promoting effects of cannabinoid receptor type 1 in human melanoma cells.

    Carpi, Sara / Fogli, Stefano / Polini, Beatrice / Montagnani, Valentina / Podestà, Adriano / Breschi, Maria Cristina / Romanini, Antonella / Stecca, Barbara / Nieri, Paola

    Toxicology in vitro : an international journal published in association with BIBRA

    2017  Volume 40, Page(s) 272–279

    Abstract: The role of endocannabinoid system in melanoma development and progression is actually not fully understood. This study was aimed at clarifying whether cannabinoid-type 1 (CB1) receptor may function as tumor-promoting or -suppressing signal in human ... ...

    Abstract The role of endocannabinoid system in melanoma development and progression is actually not fully understood. This study was aimed at clarifying whether cannabinoid-type 1 (CB1) receptor may function as tumor-promoting or -suppressing signal in human cutaneous melanoma. CB1 receptor expression was measured in human melanoma cell lines by real-time PCR. A genetic deletion of CB1 receptors in selected melanoma cells was carried out by using three different short hairpin RNAs (shRNAs). Performance of target gene silencing was verified by real-time PCR and Western blot. The effects of CB1 receptor silencing on cell growth, clonogenicity, migration capability, cell cycle progression, and activation of mitogenic signals was tested. Lentiviral shRNAs vectors targeting different regions of the human CB1 gene led to a significant reduction in CB1 receptor mRNA and a near complete loss of CB1 receptor protein, compared to control vector (LV-c). The number of viable cells, the colony-forming ability and cell migration were significantly reduced in cells transduced with CB1 lentiviral shRNAs compared to LV-c. Cell cycle analyses showed arrest at G1/S phase. p-Akt and p-ERK expression were decreased in transduced versus control cells. Findings of this study suggest that CB1 receptor might function as tumor-promoting signal in human cutaneous melanoma.
    MeSH term(s) Cell Cycle ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Humans ; MAP Kinase Signaling System ; Melanoma/genetics ; Melanoma/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, Cannabinoid, CB1/genetics ; Receptor, Cannabinoid, CB1/metabolism
    Chemical Substances Receptor, Cannabinoid, CB1 ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
    Language English
    Publishing date 2017-04
    Publishing country England
    Document type Journal Article
    ZDB-ID 639064-x
    ISSN 1879-3177 ; 0887-2333
    ISSN (online) 1879-3177
    ISSN 0887-2333
    DOI 10.1016/j.tiv.2017.01.018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2223: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  5. Article ; Online: Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations.

    Montagnani, Valentina / Benelli, Matteo / Apollo, Alessandro / Pescucci, Chiara / Licastro, Danilo / Urso, Carmelo / Gerlini, Gianni / Borgognoni, Lorenzo / Luzzatto, Lucio / Stecca, Barbara

    Oncotarget

    2016  Volume 7, Issue 21, Page(s) 30365–30378

    Abstract: Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin ( ... 4mm) melanomas. We have carried ... ...

    Abstract Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression.
    Language English
    Publishing date 2016-05-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.8758
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Hedgehog-GLI signaling drives self-renewal and tumorigenicity of human melanoma-initiating cells.

    Santini, Roberta / Vinci, Maria C / Pandolfi, Silvia / Penachioni, Junia Y / Montagnani, Valentina / Olivito, Biagio / Gattai, Riccardo / Pimpinelli, Nicola / Gerlini, Gianni / Borgognoni, Lorenzo / Stecca, Barbara

    Stem cells (Dayton, Ohio)

    2012  Volume 30, Issue 9, Page(s) 1808–1818

    Abstract: The question of whether cancer stem/tumor-initiating cells (CSC/TIC) exist in human melanomas has arisen in the last few years. Here, we have used nonadherent spheres and the aldehyde dehydrogenase (ALDH) enzymatic activity to enrich for CSC/TIC in a ... ...

    Abstract The question of whether cancer stem/tumor-initiating cells (CSC/TIC) exist in human melanomas has arisen in the last few years. Here, we have used nonadherent spheres and the aldehyde dehydrogenase (ALDH) enzymatic activity to enrich for CSC/TIC in a collection of human melanomas obtained from a broad spectrum of sites and stages. We find that melanomaspheres display extensive in vitro self-renewal ability and sustain tumor growth in vivo, generating human melanoma xenografts that recapitulate the phenotypic composition of the parental tumor. Melanomaspheres express high levels of Hedgehog (HH) pathway components and of embryonic pluripotent stem cell factors SOX2, NANOG, OCT4, and KLF4. We show that human melanomas contain a subset of cells expressing high ALDH activity (ALDH(high)), which is endowed with higher self-renewal and tumorigenic abilities than the ALDH(low) population. A good correlation between the number of ALDH(high) cells and sphere formation efficiency was observed. Notably, both pharmacological inhibition of HH signaling by the SMOOTHENED (SMO) antagonist cyclopamine and GLI antagonist GANT61 and stable expression of shRNA targeting either SMO or GLI1 result in a significant decrease in melanoma stem cell self-renewal in vitro and a reduction in the number of ALDH(high) melanoma stem cells. Finally, we show that interference with the HH-GLI pathway through lentiviral-mediated silencing of SMO and GLI1 drastically diminishes tumor initiation of ALDH(high) melanoma stem cells. In conclusion, our data indicate an essential role of the HH-GLI1 signaling in controlling self-renewal and tumor initiation of melanoma CSC/TIC. Targeting HH-GLI1 is thus predicted to reduce the melanoma stem cell compartment.
    MeSH term(s) Aldehyde Dehydrogenase/metabolism ; Animals ; Cell Growth Processes/physiology ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Female ; HEK293 Cells ; Hedgehog Proteins/antagonists & inhibitors ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism ; Humans ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Mice, Nude ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Signal Transduction ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transplantation, Heterologous ; Zinc Finger Protein GLI1
    Chemical Substances GLI1 protein, human ; Hedgehog Proteins ; Transcription Factors ; Zinc Finger Protein GLI1 ; Aldehyde Dehydrogenase (EC 1.2.1.3)
    Language English
    Publishing date 2012-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1143556-2
    ISSN 1549-4918 ; 1066-5099
    ISSN (online) 1549-4918
    ISSN 1066-5099
    DOI 10.1002/stem.1160
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1894: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  7. Article ; Online: Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells.

    Vitiello, Marianna / Tuccoli, Andrea / D'Aurizio, Romina / Sarti, Samanta / Giannecchini, Laura / Lubrano, Simone / Marranci, Andrea / Evangelista, Monica / Peppicelli, Silvia / Ippolito, Chiara / Barravecchia, Ivana / Guzzolino, Elena / Montagnani, Valentina / Gowen, Michael / Mercoledi, Elisa / Mercatanti, Alberto / Comelli, Laura / Gurrieri, Salvatore / Wu, Lawrence W /
    Ope, Omotayo / Flaherty, Keith / Boland, Genevieve M / Hammond, Marc R / Kwong, Lawrence / Chiariello, Mario / Stecca, Barbara / Zhang, Gao / Salvetti, Alessandra / Angeloni, Debora / Pitto, Letizia / Calorini, Lido / Chiorino, Giovanna / Pellegrini, Marco / Herlyn, Meenhard / Osman, Iman / Poliseno, Laura

    Oncotarget

    2017  Volume 8, Issue 15, Page(s) 25395–25417

    Abstract: Despite increasing amounts of experimental evidence depicting the involvement of non-coding RNAs in cancer, the study of BRAFV600E-regulated genes has thus far focused mainly on protein-coding ones. Here, we identify and study the microRNAs that ... ...

    Abstract Despite increasing amounts of experimental evidence depicting the involvement of non-coding RNAs in cancer, the study of BRAFV600E-regulated genes has thus far focused mainly on protein-coding ones. Here, we identify and study the microRNAs that BRAFV600E regulates through the ERK pathway.By performing small RNA sequencing on A375 melanoma cells and a vemurafenib-resistant clone that was taken as negative control, we discover miR-204 and miR-211 as the miRNAs most induced by vemurafenib. We also demonstrate that, although belonging to the same family, these two miRNAs have distinctive features. miR-204 is under the control of STAT3 and its expression is induced in amelanotic melanoma cells, where it acts as an effector of vemurafenib's anti-motility activity by targeting AP1S2. Conversely, miR-211, a known transcriptional target of MITF, is induced in melanotic melanoma cells, where it targets EDEM1 and consequently impairs the degradation of TYROSINASE (TYR) through the ER-associated degradation (ERAD) pathway. In doing so, miR-211 serves as an effector of vemurafenib's pro-pigmentation activity. We also show that such an increase in pigmentation in turn represents an adaptive response that needs to be overcome using appropriate inhibitors in order to increase the efficacy of vemurafenib.In summary, we unveil the distinct and context-dependent activities exerted by miR-204 family members in melanoma cells. Our work challenges the widely accepted "same miRNA family = same function" rule and provides a rationale for a novel treatment strategy for melanotic melanomas that is based on the combination of ERK pathway inhibitors with pigmentation inhibitors.
    MeSH term(s) Adaptor Protein Complex sigma Subunits/genetics ; Adaptor Protein Complex sigma Subunits/metabolism ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Humans ; Indoles/pharmacology ; MAP Kinase Signaling System ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Melanoma, Amelanotic/drug therapy ; Melanoma, Amelanotic/genetics ; Melanoma, Amelanotic/metabolism ; Melanoma, Amelanotic/pathology ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Sulfonamides/pharmacology ; Transfection ; Vemurafenib
    Chemical Substances AP1S2 protein, human ; Adaptor Protein Complex sigma Subunits ; Antineoplastic Agents ; EDEM1 protein, human ; Indoles ; MIRN204 microRNA, human ; MIRN211 microRNA, human ; Membrane Proteins ; MicroRNAs ; STAT3 Transcription Factor ; STAT3 protein, human ; Sulfonamides ; Vemurafenib (207SMY3FQT) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2017-04-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.15915
    Database MEDical Literature Analysis and Retrieval System OnLINE

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