MicroRNAs and adhesion molecules involved in tumor progression
Daniela Taverna
daniela.taverna@unito.it

 

Description

(A) One of our main research goals is the identification and characterization of microRNAs (miRNAs) involved in tumor progression, referring in particular to breast cancer and melanoma. Human tumor samples or metastases derived from patients that relapsed or not and differentially malignant tumor cell lines are used to identify miRNAs involved in tumor progression. In this way, we recently identifed a signature that can be used to classify breast tumors and predict the outcome of the deseases. In addition, we identified miR-214, overexpressed in malignant melanomas, and proved its pro-metastatic function. On other hand, we found low expression of miR-148b in relapsed breast tumors and revealed its anti-metastatic role. Generally, in our laboratory, relevant miRNAs are overexpressed or silenced in cell lines and their biological function is evaluated in terms of proliferation, apoptosis, tumor formation and in particular migration/invasion and metastasis dissemination by performing in vitro (cell culture) and in vivo (mouse) experiments. Since miRNAs regulate protein-coding gene expression it is essential to identify the miRNA target genes responsible of certain biological funcitons. For this purpose we use protein-coding gene expression profiles and computational predictions with several algorithms. The targets are validated using luciferase reporter vectors containing 3’UTR sequences of the potential target genes and by western blot analyses. We are also generating trangenic and knock out mouse models for one or more identified miRNAs and use miRNAs as targets for gene therapy in tumors.

Examples of results in breast cancer:

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 src=(B) Another line of research going on in our laboratory regards the role of the AP-2 transcription factors and its gene targets in adenocarcinoma progression. A role for AP-2 in cancer is suggested by many evidences. First, AP-2 is lost in metastatic melanomas, where it acts as a tumor suppressor gene; second, AP-2 proteins are essential regulators of a number of genes central to cancer, e.g. ERBB2, E-cadherin, VEGF, p21WAF/CIP and others; third, AP-2 interact with p53 and myc proteins at different promoters. The AP-2 family consists of five members that can form homo- or heterodimers and transactivate many target genes by binding to GC-rich consensus sequences present in their promoter regions and orchestrate a variety of cell processes including apoptosis, cell growth, cell adhesion and tissue differentiation. We recently overexpressed and silenced (RNAi) two AP-2 family members, AP-2alpha and/or AP-2gamma in various adenocarcinoma cell lines and observed that both AP-2 members act as tumor suppressors during the first steps of tumorigenesis, in fact in absence of AP-2 cells grow faster in soft agar models or when injected in immunodeficient mice (xenotransplants). However AP-2 silencing reduces cell motility and invasion. By performing microarray analysis we identified some players that modulate cell motility or invasion such as ESDN, EREG and CXCL2. We are now characterizing those players and their transcriptional regulation by AP-2.

 

 

Selected publications

 

Penna E, Orso F, Cimino D, Vercellino I, Grassi E, Quaglino E, Turco E, Taverna D. miR-214 coordinates melanoma progression by upregulating ALCAM through TFAP2 and miR-148b downmodulation. Cancer Res. 2013 May 10. [Epub ahead of print]

Arigoni M, Barutello G, Riccardo F, Ercole E, Cantarella D, Orso F, Conti L, Lanzardo S, Taverna D, Merighi I, Calogero RA, Cavallo F, Quaglino E. miR-135b Coordinates Progression of ErbB2-Driven Mammary Carcinomas through Suppression of MID1 and MTCH2. Am J Pathol. 2013 Jun;182(6):2058-70.

 Elsarraj HS, Hong Y, Valdez K, Carletti M, Salah SM, Raimo M, Taverna D, Prochasson P, Bharadwaj U, Tweardy DJ, Christenson LK, Behbod F. Novel role of microRNA146b in promoting mammary alveolar progenitor cell maintenance. J Cell Sci. 2013 Apr 9. [Epub ahead of print]

 

D. Cimino, C. De Pittà, F. Orso, M. Zampini, S. Casara, E. Penna, E. Quaglino, M. Forni, C. Damasco, E. Pinatel, R. Ponzone, C. Romualdi, C. Brisken, M. De Bortoli, N. Biglia, P. Provero, G. Lanfranchi, D. Taverna (2012). miR148b is a major coordinator of breast cancer progression in a relapse-associated microRNA signature by targeting ITGA5, ROCK1, PIK3CA, NRAS and CSF1. THE FASEB JOURNAL, 2013 Mar;27(3):1223-35. doi: 10.1096/fj.12-214692. Epub 2012 Dec 11.

Bisaro B, Montani M, Konstantinidou G, Marchini C, Pietrella L, Iezzi M, Galie M, Orso F, Camporeale A, Colombo SM, Di Stefano P, Tornillo G, Camacho-Leal MD, Turco E, Taverna D, Cabodi S, Amici A, Defilippi P. p130Cas/Cyclooxygenase-2 axis in the control of mesenchymal plasticity of breast cancer cells. Breast Cancer Res. 2012 Oct 26;14(5):R137.

Osella-Abate S, Novelli M, Quaglino P, Orso F, Ubezio B, Tomasini C, Berardengo E, Bernengo MG, Taverna D. Expression of AP-2α, AP-2γ and ESDN in primary melanomas: Correlation with histopathological features and potential prognostic value. J Dermatol Sci. 2012 Dec;68(3):202-4. doi: 10.1016/j.jdermsci.2012.09.008. Epub 2012 Sep 18.

Gagliardi PA, di Blasio L, Orso F, Seano G, Sessa R, Taverna D, Bussolino F, Primo L 3-phosphoinositide-dependent kinase 1 controls breast tumor growth in a kinase-dependent but Akt-independent manner. Neoplasia. 2012 Aug;14(8):719-31.

Courtin A, Communal L, Vilasco M, Cimino D, Mourra N, de Bortoli M, Taverna D, Faussat AM, Chaouat M, Forgez P, Gompel A. Glucocorticoid receptor activity discriminates between progesterone and medroxyprogesterone acetate effects in breast cells. Breast Cancer Res Treat. 2012 Jan;131(1):49-63. Epub 2011 Feb 19.

Tombolan L, Orso F, Guzzardo V, Casara S, Zin A, Bonora M, Romualdi C, Giorgi C, Bisogno G, Alaggio R, Pinton P, De Pittà C, Taverna D, Rosolen A, Lanfranchi G. High IGFBP2 expression correlates with tumor severity in pediatric rhabdomyosarcoma. Am J Pathol. 2011 Nov;179(5):2611-24. doi: 10.1016/j.ajpath.2011.07.018. Epub 2011 Sep 13.

Penna E, Orso F, Cimino D, Tenaglia E, Lembo A, Quaglino E, Poliseno L, Haimovic A, Osella-Abate S, De Pittà C, Pinatel E, Stadler MB, Provero P, Bernengo MG, Osman I, Taverna D. microRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C. EMBO J. 2011 May 18;30(10):1990-2007. Epub 2011 Apr 5.

Friard O, Re A, Taverna D, De Bortoli M and Corà M. CircuitsDB: a database of mixed microRNA / Transcription. BMC Bioinformatics, 2010, 11:435-445. 

Dentelli P, Rosso A, Orso F, Taverna D and Maria Brizzi MF. miR-222 controls neovascularization by regulating STAT5A expression. Arteriosclerosis, Thrombosis and Vascular Biology, 2010, 30:1562-1568 

Orso F, Corà D, Ubezio B, De Bortoli M, Provero P, M. Caselle and Taverna D. Analysis of the regulatatory regions of AP-2amodulated genes. BMC Genomics, 2010, 11: 355. 

Cabodi S. and Taverna D. Interfering with inflammation: a new strategy to block breast cancer self-renewal and progression? Breast Cancer Research, 2010, 12:305. 

Thewes V, Orso F,  Jäger R, Eckert D, Kirfel G, Garbe G, Taverna D and Schorle H. Interference with Activator Protein-2 transcription factors leads to induction of apoptosis and an increase in chemo- and radiation- sensitivity in breast cancer cells. BMC Cancer, 2010, 10:192

Orso F, Jaeger R, Calogero RA, Schorle H, Sismondi P, De Bortoli M and Taverna D. AP-2ALPHA REGULATES MIGRATION OF GN-11 NEURONS VIA A SPECIFIC GENETIC PROGRAM INVOLVING THE AXL RECEPTOR TYROSINE KINASE. BMC Biology, 2009, 7:25.

Re A, Corà D, Taverna D and Caselle M. GENOME WIDE SURVEY OF MICRO RNA-TRANSCRIPTION FACTOR REGULATORY CIRCUITS IN HUMAN. Mol. BioSyst., 2009, 5: 854-867.

Dentelli P, Trombetta A, Togliatto G, Zeoli A, Rosso A, Uberti B, Orso F, Taverna D, Pegoraro L, Brizzi MF. FORMATION OF STAT5/PPAR{GAMMA} TRANSCRIPTIONAL COMPLEX MODULATES ANGIOGENIC CELL BIOAVAILABILITY IN DIABETES. Arterioscler Thromb Vasc Biol.,  2009 Jan;29(1):114-20.

Cimino D, Fuso L, Sfiligoi C, Biglia N, Ponzone R, Maggiorotto F, Russo G, Cicatiello L, Weisz A, Taverna D, Sismondi P, De Bortoli M. IDENTIFICATION OF NEW GENES ASSOCIATED WITH BREAST CANCER PROGRESSION BY GENE EXPRESSION ANALYSIS OF PREDEFINED SETS OF NEOPLASTIC TISSUES. Int J Cancer. 2008 Sep 15;123(6):1327-38.

Orso F, Penna E, Cimino D, Astanina E, Maione F, Valdembri D, Giraudo E, Serini G, Sismondi P, De Bortoli M, Taverna D. AP-2ALPHA AND AP-2GAMMA REGULATE TUMOR PROGRESSION VIA SPECIFIC GENETIC PROGRAMS. FASEB J. 2008 Aug;22(8):2702-14. Epub 2008 Apr 28.

Orso F, Fassetta M, Penna E, Solero A, De Filippo K, Sismondi P, De Bortoli M, Taverna D. THE AP-2ALPHA TRANSCRIPTION FACTOR REGULATES TUMOR CELL MIGRATION AND APOPTOSIS. Adv Exp Med Biol. 2007;604:87-95.

Taverna D, Crowley D, Connolly M, Bronson RO and Richard Hynes. (2005). A DIRECT TEST OF POTENTIAL ROLES FOR BETA3 AND BETA5 INTEGRINS IN GROWTH AND METASTASIS OF MURINE MAMMARY CARCINOMAS. Cancer Res. Nov 15; 65(22):10324-9.

Taverna D, Moher H, Crowley D, Borsig L, Varki A, Hynes RO. (2004). INCREASED PRIMARY TUMOR GROWTH IN MICE NULL FOR BETA3- OR BETA3/BETA5-INTEGRINS OR SELECTINS. Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):763-8.

Reynolds LE, Wyder L, Lively JC, Taverna D, Robinson SD, Huang X, Sheppard D, Hynes RO, Hodivala-Dilke KM. Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med. 2002 Jan;8(1):27-34.

 

 

 

Unit members

 

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Orso Francesca PostDoc francesca.orso@unito.it
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Penna Elisa PostDoc elisa.penna@unito.it
  src= Raimo Monica PhD Student

monica.raimo@gmail.com 

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Coppo  Roberto PhD Student copporoberto@yahoo.it

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Quirico Lorena

PhD Student

quilore85@yahoo.it

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 Curto  Rosalia Undergraduate Student rosalia.curto@studenti.unito.it

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 Federico   Virga

Undergraduate Student

federico.virga@studenti.unito.it 

 

 

 

       

 

 

 

 

 

 

 

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