Manuela Ferracin

Publications (53) View all

• Article: Anti-CD38 antibody therapy: windows of opportunity yielded by the functional characteristics of the target molecule.

  Antonella Chillemi, Gianluca Zaccarello, Valeria Quarona, Manuela Ferracin, Chiara Ghimenti, Massimo Massaia, Alberto L Horenstein, Fabio Malavasi
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  ABSTRACT: In vivo use of monoclonal antibodies (mAbs) has become a mainstay of routine clinical practice in the treatment of various human diseases. A number of molecules can serve as targets, according to the condition being treated. Now entering human clinical trials, CD38 is a particularly attractive target because of its peculiar pattern of expression and its twin role as receptor and ectoenzyme. This review provides a range of analytical perspectives on the current progress in and challenges to anti-CD38 mAb therapy. We present a synopsis of the evidence available on CD38, particularly in myeloma and chronic lymphocytic leukemia. Our aim is to make the data from basic science helpful and accessible to a diverse clinical audience and, at the same time, to improve its potential for in vivo use.The topics covered include tissue distribution and signal implementation by mAb ligation and the possibility of increasing cell density on target cells by exploiting information about the molecule's regulation in combination with drugs approved for in vivo use. Also analyzed is the behavior of CD38 as an enzyme: CD38 is a component of a pathway leading to the production of adenosine in the tumor microenvironment, thus inducing local anergy. Consequently, not only might CD38 be a prime target for mAb-mediated therapy, but its functional block may contribute to general improvement in cancer immunotherapy and outcomes.
  Molecular Medicine 04/2013; · 3.76 Impact Factor
• Source

  Available from: Manuela Ferracin

  Article: The Role of Micro-RNAs in Rheumatic Diseases: An Update

  Giovanni Ciancio, Manuela Ferracin, Massimo Negrini, Marcello Govoni
  Intech. 01/2013;
• Article: miR-126&126* Restored Expressions Play a Tumor Suppressor Role by Directly Regulating ADAM9 and MMP7 in Melanoma.

  Nadia Felli, Federica Felicetti, Anna Maria Lustri, M Cristina Errico, Lisabianca Bottero, Alessio Cannistraci, Alessandra De Feo, Marina Petrini, Francesca Pedini, Mauro Biffoni, Ester Alvino, Massimo Negrini, Manuela Ferracin, Gianfranco Mattia, Alessandra Carè
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  ABSTRACT: The abnormal expression of several microRNAs has a causal role in tumorigenesis with either antineoplastic or oncogenic functions. Here we demonstrated that miR-126 and miR-126* play a tumor suppressor role in human melanoma through the direct or indirect repression of several key oncogenic molecules. The expression levels of miR-126&126* were elevated in normal melanocytes and primary melanoma cell lines, whereas they markedly declined in metastatic cells. Indeed, the restored expression of miR-126&126* in two advanced melanoma cell lines was accompanied by a significant reduction of proliferation, invasion and chemotaxis in vitro as well as of growth and dissemination in vivo. In accordance, the reverse functional effects were obtained by knocking down miR-126&126* by transfecting antisense LNA oligonucleotides in melanoma cells. Looking for the effectors of these antineoplastic functions, we identified ADAM9 and MMP7, two metalloproteases playing a pivotal role in melanoma progression, as direct targets of miR-126&126*. In addition, as ADAM9 and MMP7 share a role in the proteolytic cleavage of the HB-EGF precursor, we looked for the effectiveness of this regulatory pathway in melanoma, confirming the decrease of HB-EGF activation as a consequence of miR-126&126*-dependent downmodulation of ADAM9 and MMP7. Finally, gene profile analyses showed that miR-126&126* reexpression was sufficient to inactivate other key signaling pathways involved in the oncogenic transformation, as PI3K/AKT and MAPK, and to restore melanogenesis, as indicated by KIT/MITF/TYR induction. In view of this miR-126&126* wide-ranging action, we believe that the replacement of these microRNAs might be considered a promising therapeutic approach.
  PLoS ONE 01/2013; 8(2):e56824. · 4.09 Impact Factor
• Article: miR-221 affects multiple cancer pathways by modulating the level of hundreds messenger RNAs.

  Laura Lupini, Cristian Bassi, Manuela Ferracin, Nenad Bartonicek, Lucilla D'Abundo, Barbara Zagatti, Elisa Callegari, Gentian Musa, Farzaneh Moshiri, Laura Gramantieri, Fernando J Corrales, Anton J Enright, Silvia Sabbioni, Massimo Negrini
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  ABSTRACT: microRNA miR-221 is frequently over-expressed in a variety of human neoplasms. Aim of this study was to identify new miR-221 gene targets to improve our understanding on the molecular tumor-promoting mechanisms affected by miR-221. Gene expression profiling of miR-221-transfected-SNU-398 cells was analyzed by the Sylamer algorithm to verify the enrichment of miR-221 targets among down-modulated genes. This analysis revealed that enforced expression of miR-221 in SNU-398 cells caused the down-regulation of 602 mRNAs carrying sequences homologous to miR-221 seed sequence within their 3'UTRs. Pathways analysis performed on these genes revealed their prominent involvement in cell proliferation and apoptosis. Activation of E2F, MYC, NFkB, and β-catenin pathways was experimentally proven. Some of the new miR-221 target genes, including RB1, WEE1 (cell cycle inhibitors), APAF1 (pro-apoptotic), ANXA1, CTCF (transcriptional repressor), were individually validated as miR-221 targets in SNU-398, HepG2, and HEK293 cell lines. By identifying a large set of miR-221 gene targets, this study improves our knowledge about miR-221 molecular mechanisms involved in tumorigenesis. The modulation of mRNA level of 602 genes confirms the ability of miR-221 to promote cancer by affecting multiple oncogenic pathways.
  Frontiers in genetics. 01/2013; 4:64.
• Article: Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model.

  Elisa Callegari, Bahaeldin K Elamin, Ferdinando Giannone, Maddalena Milazzo, Giuseppe Altavilla, Francesca Fornari, Luciano Giacomelli, Lucilla D'Abundo, Manuela Ferracin, Cristian Bassi, Barbara Zagatti, Fabio Corrà, Elena Miotto, Laura Lupini, Luigi Bolondi, Laura Gramantieri, Carlo M Croce, Silvia Sabbioni, Massimo Negrini
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  ABSTRACT: MicroRNA-221 (miR-221) is one of the most frequently and consistently up-regulated microRNAs (miRNAs) in human cancer. It has been hypothesized that miR-221 may act as a tumor promoter. To demonstrate this, we developed a transgenic (TG) mouse model that exhibits an inappropriate overexpression of miR-221 in the liver. Immunoblotting and immunostaining confirmed a concomitant down-regulation of miR-221 target proteins. This TG model is characterized by the emergence of spontaneous nodular liver lesions in approximately 50% of male mice and by a strong acceleration of tumor development in 100% of mice treated with diethylnitrosamine. Similarly to human hepatocellular carcinoma, tumors are characterized by a further increase in miR-221 expression and a concomitant inhibition of its target protein-coding genes (i.e., cyclin-dependent kinase inhibitor [Cdkn]1b/p27, Cdkn1c/p57, and B-cell lymphoma 2-modifying factor). To validate the tumor-promoting effect of miR-221, we showed that in vivo delivery of anti-miR-221 oligonucleotides leads to a significant reduction of the number and size of tumor nodules. CONCLUSIONS: This study not only establishes that miR-221 can promote liver tumorigenicity, but it also establishes a valuable animal model to perform preclinical investigations for the use of anti-miRNA approaches aimed at liver cancer therapy.
  Hepatology 04/2012; 56(3):1025-33. · 11.66 Impact Factor