RESEARCH ACTIVITY
Our research group aims at the characterization of putative tumor-suppressor genes from the peritelomeric region of the long arm of human chromosome 6. A detailed physical map within the 6q27 region was assembled from a 2 cM genomic interval that was previously shown to bear frequent deletions and chromosomal rearrangements in several human malignancies. Gene-trapping approaches, combined with in silico analyses, led to identification of several genes within the reported region of minimal deletion. Among the genes located in this region, our group focused his attention on the RNASET2 gene and a detailed functional analysis unveiled a striking anti-tumorigenic and anti-metastatic activity for this gene, which is now presumed to be acting as a “tumor antagonizing” gene for ovarian cancer and melanoma. In particular, we have reported a remarkable RNASET2-mediated in vivo tumor suppression in two independent models of human ovarian cancer, through xenograft-based experiments in nude mice. Strikingly, the catalytic activity of the RNASET2 protein turned out to be dispensable for its anti-tumorigenic role, suggesting a highly pleiotropic function for this gene.
In recent years, our group discovered a central role of cells form the monocyte/macrophages lineage in RNASET2-mediated tumor suppression. Indeed, RNASET2-mediated tumor suppression was shown to occur in vivo through modification of the cellular microenvironment and the recruitment of immunocompetent cells toward the site of tumor growth by extracellular RNASET2 protein, suggesting a non-cell autonomous oncosuppressive role for this gene.
However, more recent data from our lab indicate the occurrence of an equally strong cell-autonomous oncosuppressive role for RNASET2, which is carried out at the level of several cancer-related biological processes, such as cell cytoskeleton organization, cell differentiation and apoptosis.
Finally, we recently defined RNASET2 as a powerfull stress response gene, whose expression is largely increased following the application of a wide range of cellular stresses.
Taken together, these data led us to propose RNASET2 as a member of the growing family of alarmins, danger-signaling molecules that are widely deployed by eukaryotic cells to prevent cellular damages coming from different sources.
We are currently trying to evaluate the role of the microenvironment on tumor suppression mediated by RNASET2, to find out which protein portion is responsible for its antitumorigenic activity and to better understand the biological processes in which the RNASET2 protein is involved both inside and outside the cell.
We reckon that, besides improvements in the theoretical aspects aimed at widening the operational definition of tumor suppressor genes, the in-depth characterization of the RNASET2 gene could provide useful information that can be exploited in a more clinically oriented avenue.
Staff
Roberto Taramelli
(Full Professor of Genetics). Mail to: roberto.taramelli@uninsubria.it
Francesco Acquati
(Associate Professor of Genetics). Mail to: francesco.acquati@uninsubria.it
Dr. Laura Monti
(Lab technician). Mail to: laura.monti@uninsubria.it
Papers
2018
Uccella S, La Rosa S, Scaldaferri D, Monti L, Maragliano R, Sorrenti E, Gariboldi M, Taramelli R, Sessa F, Acquati F. 2018. New insights into hypoxia-related. mechanisms involved in different microvascular patterns of bronchopulmonary carcinoids and poorly differentiated neuroendocrine carcinomas. Role of ribonuclease T2 (RNASET2) and HIF-1 alpha. Hum Pathol, 12. pii: S0046-8177(18)30163-1. doi:110.1016/j.humpath.2018.04.028
2017
Baranzini N, Pedrini E, Girardello R, Tettamanti G, de Eguileor M, Taramelli R, Acquati F, Grimaldi A. 2017. Human recombinant RNASET2-induced inflammatory response and connective tissue remodeling in the medicinal leech. Cell Tissue Res., 368(2):337-351. doi:10.1007/s00441-016-2557-9
Zhou JX, Taramelli R, Pedrini E, Knijnenburg T, Huang S. 2017. Extracting Intercellular Signaling Network of Cancer Tissues using Ligand-Receptor Expression Patterns from Whole-tumor and Single-cell Transcriptomes. Sci Rep. 7(1):8815. doi:10.1038/s41598-017-09307-w
2016
Turconi G, Scaldaferri D, Fabbri M, Monti L, Lualdi M, Pedrini E, Gribaldo L, Taramelli R, Acquati F. 2016. RNASET2 silencing affects miRNAs and target gene expression pattern in a human ovarian cancer cell model. Int J Oncol, 49(6):2637-2646. doi:110.3892/ijo.2016.3763
2015
Lualdi M, Pedrini E, Petroni F, Näsman J, Lindqvist C, Scaldaferri D, Taramelli R, Inforzato A, Acquati F. New Strategies for Expression and Purification of Recombinant Human RNASET2 Protein in Pichia pastoris. Mol. Biotechnol, 57(6):513-25. doi:110.1007/s12033-015-9845-6
Lualdi M, Pedrini E, Rea K, Monti L, Scaldaferri D, Gariboldi M, Camporeale A, Ghia P, Monti E, Tomassetti A, Acquati F, Taramelli R. 2015. Pleiotropic modes of action in tumor cells of RNASET2, an evolutionary highly conserved extracellular RNase. Oncotarget., 6(10):7851-765.
2013
Acquati F, Lualdi M, Bertilaccio S, Monti L, Turconi G, Fabbri M, Grimaldi A, Anselmo A, Inforzato A, Collotta A, Cimetti L, Riva C, Gribaldo L, Ghia P, Taramelli R. 2013. Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis. Proc Natl Acad Sci U S A, 110(20):8140-8145. doi:10.1073/pnas.1222079110
2012
Banfi S, Monti L, Acquati F, Tettamanti G, de Eguileor M, Grimaldi A. 2012. Muscle development and differentiation in the urodele Ambystoma mexicanum. Dev Growth Differ, 54(4):489-502. doi:10.1111/j.1440-169X.2012.01338.x
Patel S, Chen H, Monti L, Gould E, Haralambieva E, Schmid J, Toomey D, Woessmann W, Roncador G, Hatton CS, Liggins AP, Taramelli R, Banham AH, Acquati F, Murphy D, Pulford K. 2012. RNASET2–an autoantigen in anaplastic large cell lymphoma identified by protein array analysis. J Proteomics. 2012 Sep 18;75(17):5279-92. doi:10.1016/j.jprot.2012.06.009
Vidalino L, Monti L, Haase A, Moro A, Acquati F, Taramelli R, Macchi P. 2012. Intracellular trafficking of RNASET2, a novel component of P-bodies. Biol Cell., 104(1):13-21. doi:10.1111/boc.201100092
2011
Acquati F, Monti L, Lualdi M, Fabbri M, Sacco MG, Gribaldo L, Taramelli R. 2011. Molecular signature induced by RNASET2, a tumor antagonizing gene, in ovarian cancer cells. Oncotarget, 2(6):477-484.
Acquati F, Bertilaccio S, Grimaldi A, Monti L, Cinquetti R, Bonetti P, Lualdi M, Vidalino L, Fabbri M, Sacco MG, van Rooijen N, Campomenosi P, Vigetti D, Passi A, Riva C, Capella C, Sanvito F, Doglioni C, Gribaldo L, Macchi P, Sica A, Noonan DM, Ghia P, Taramelli R. 2011. Microenvironmental control of malignancy exerted by RNASET2, a widely conserved extracellular RNase. Proc Natl Acad Sci U S A., 108(3):1104-1109. doi:10.1073/pnas.1013746108
Campomenosi P, Cinquetti R, Tallarita E, Lindqvist C, Raimondi I, Grassi P, Näsman J, Dell A, Haslam SM, Taramelli R, Acquati F. 2011. Comparison of the baculovirus-insect cell and Pichia pastoris heterologous systems for the expression of the human tumor suppressor protein RNASET2. Biotechnol Appl Biochem, 58(1):39-49. doi:10.1002/bab.7
2009
Badi I, Cinquetti R, Frascoli M, Parolini C, Chiesa G, Taramelli R, Acquati F. 2009. Intracellular ANKRD1 protein levels are regulated by 26S proteasome-mediated degradation. FEBS Lett., 583(15):2486-92. doi:10.1016/j.febslet.2009.07.001
Monti L, Cinquetti R, Guffanti A, Nicassio F, Cremona M, Lavorgna G, Bianchi F, Vignati F, Cittaro D, Taramelli R, Acquati F. 2009. In silico prediction and experimental validation of natural antisense transcripts in two cancer-associated regions of human chromosome 6. Int J Oncol, 34(4):1099-108.
2008
Cinquetti R, Badi I, Campione M, Bortoletto E, Chiesa G, Parolini C, Camesasca C, Russo A, Taramelli R, Acquati F. 2008. Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return. Hum Mutat., 29(4):468-474. doi: 10.1002/humu.20711
Finzi G, Franzi F, Placidi C, Acquati F, Palumbo E, Russo A, Taramelli R, Sessa F, La Rosa S. 2008. BACE2 is stored in secretory granules of mouse and rat pancreatic beta cells. Ultrastruct Pathol. 2008 Nov-Dec;32(6):246-51. doi:10.1080/01913120802486217
Grimaldi A, Tettamanti G, Acquati F, Bossi E, Guidali ML, Banfi S, Monti L, Valvassori R, de Eguileor M. 2008. A hedgehog homolog is involved in muscle formation and organization of Sepia officinalis (mollusca) mantle. Dev Dyn, 237(3):659-71. doi: 10.1002/dvdy.21453
Monti L, Rodolfo M, Lo Russo G, Noonan D, Acquati F, Taramelli R. 2008. RNASET2 as a tumor antagonizing gene in a melanoma cancer model. Oncol Res. 2008;17(2):69-74. Erratum in: Oncol Res, 7(4):191. Rudolfo, Monica [corrected to Rodolfo, Monica].
Muller H, Acquati F. 2008. Topological properties of co-occurrence networks in published gene expression signatures. Bioinform Biol Insights, 2:203-213.
2007
Taramelli R. 2007. The genetic bases of cancer. Surg Oncol, 16(Suppl 1):S1-2
2006
Campomenosi P, Salis S, Lindqvist C, Mariani D, Nordström T, Acquati F, Taramelli R. 2006. Characterization of RNASET2, the first human member of the Rh/T2/S family of glycoproteins. Arch Biochem Biophys, 449(1-2):17-26
2005
Acquati F, Possati L, Ferrante L, Campomenosi P, Talevi S, Bardelli S, Margiotta C, Russo A, Bortoletto E, Rocchetti R, Calza R, Cinquetti R, Monti L, Salis S, Barbanti-Brodano G, Taramelli R. 2005. Tumor and metastasis suppression by the human RNASET2 gene. Int J Oncol., 26(5):1159-68.
Diodovich C, Malerba I, Ferrario D, Bowe G, Bianchi MG, Acquati F, Taramelli R, Parent-Massin D, Gribaldo L. 2005. Gene and protein expressions in human cord blood cells after exposure to acrylonitrile. J Biochem Mol Toxicol., 19(4):204-212.
2004
Taramelli R, Acquati F. 2004. The human genome project and the discovery of genetic determinants of cancer susceptibility. Eur J Cancer, 40(17):2537-43.
Diodovich C, Bianchi MG, Bowe G, Acquati F, Taramelli R, Parent-Massin D, Gribaldo L. 2004. Response of human cord blood cells to styrene exposure: evaluation of its effects on apoptosis and gene expression by genomic technology. Toxicology, 200(2-3):145-57.
2003
Diodovich C, Malerba I, Bowe G, Acquati F, Bianchi MG, Taramelli R, Parent-Massin D, Gribaldo L. 2003. Naphthalene exposure: effects on gene expression and proliferation in human cord blood cells. J Biochem Mol Toxicol., 7(5):286-94.
Cinquetti R, Mazzotti F, Acquati F, Gornati R, Sabbioni E, Taramelli R, Bernardini G. 2003. Influence of metal ions on gene expression of BALB 3T3 fibroblasts. Gene, 318:83-89.
Tibiletti MG, Bernasconi B, Taborelli M, Facco C, Riva C, Capella C, Franchi M, Binelli G, Acquati F, Taramelli R. 2003. Genetic and cytogenetic observations among different types of ovarian tumors are compatible with a progression model underlying ovarian tumorigenesis. Cancer Genet Cytogenet., 146(2):145-153.
2001
Tibiletti MG, Bernasconi B, Furlan D, Bressan P, Cerutti R, Facco C, Franchi M, Riva C, Cinquetti R, Capella C, Taramelli R. 2001. Chromosome 6 abnormalities in ovarian surface epithelial tumors of borderline malignancy suggest a genetic continuum in the progression model of ovarian neoplasms. Clin Cancer Res, 7(11):3404-3409.
Politi A, Mameli S, Acquati F, Galli M, Zerboni S, Michi R, Ferrari G. 2001. Acute myocardial infarction during labor: report of a case and review of the literature. Ital Heart J Suppl, 2(7):795-798.
Acquati F, Morelli C, Cinquetti R, Bianchi MG, Porrini D, Varesco L, Gismondi V, Rocchetti R, Talevi S, Possati L, Magnanini C, Tibiletti MG, Bernasconi B, Daidone MG, Shridhar V, Smith DI, Negrini M, Barbanti-Brodano G, Taramelli R. 2001. Cloning and characterization of a senescence inducing and class II tumor suppressor gene in ovarian carcinoma at chromosome region 6q27. Oncogene, 20(8):980-988.
Acquati F, Nucci C, Bianchi MG, Gorletta T, Taramelli R. 2001. Molecular cloning, tissue distribution, and chromosomal localization of the human homolog of the R2/Th/Stylar ribonuclease gene family. Methods Mol Biol., 160:87-101.
2000
Corrado G, Santarone M, Beretta S, Tadeo G, Tagliagambe LM, Foglia-Manzillo G, Spata M, Miglierina E, Acquati F, Santarone M. 2000. Early cardioversion of atrial fibrillation and atrial flutter guided by transoesophageal echocardiography: a single centre 8.5-year experience. Europace, 2(2):119-126.
Gasparini M, Mantica M, Brignole M, Coltorti F, Galimberti P, Gianfranchi L, Menozzi C, Magenta G, Delise P, Proclemer A, Tognarini S, Ometto R, Acquati F, Mantovan R. 2000. Long-term follow-up after atrioventricular nodal ablation and pacing: low incidence of sudden cardiac death. Pacing Clin Electrophysiol., 23(11-Pt 2):1925-1929.
Acquati F, Russo A, Taramelli R, Tibiletti MG, Taborelli M, Camesasca C, Papa M. 2000. Nonsyndromic total anomalous venous return associated with a de novo translocation inolving chromosomes 10 and 21 t(10;21)(q23.1;q11.2). Am J Med Genet., 95(3):285-286.
Vigetti D, Monetti C, Acquati F, Taramelli R, Bernardini G. 2000. Human allantoicase gene: cDNA cloning, genomic organization and chromosome localization. Gene, 256(1-2):253-260.
Vigetti D, Monetti C, Pollegioni L, Taramelli R, Bernardini G. 2000. Xenopus allantoicase: molecular cloning, enzymatic activity and developmental expression. Arch Biochem Biophys., 379(1):90-96.
Tibiletti MG, Sessa F, Bernasconi B, Cerutti R, Broggi B, Furlan D, Acquati F, Bianchi M, Russo A, Capella C, Taramelli R. 2000. A large 6q deletion is a common cytogenetic alteration in fibroadenomas, pre-malignant lesions, and carcinomas of the breast. Clin Cancer Res., 6(4):1422-1431.
Acquati F, Accarino M, Nucci C, Fumagalli P, Jovine L, Ottolenghi S, Taramelli R. 2000. The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region. FEBS Lett., 468(1):59-64.
1999
Sabbioni S, Veronese A, Trubia M, Taramelli R, Barbanti-Brodano G, Croce CM, Negrini M. 1999. Exon structure and promoter identification of STIM1 (alias GOK), a human gene causing growth arrest of the human tumor cell lines G401 and RD. Cytogenet Cell Genet., 86(3-4):214-218.
Tao R, Acquati F, Marcovina SM, Hobbs HH. 1999. Human growth hormone increases apo(a) expression in transgenic mice. Arterioscler Thromb Vasc Biol., 19(10):2439-2447.
Gasparini M, Mantica M, Brignole M, Gianfranchi L, Menozzi C, Pizzetti F, Magenta G, Delise P, Proclemer A, Tognarin S, Ometto R, Acquati F, Mantovan R, Turco P, De Ferrari GM. 1999. Thromboembolism after atrioventricular node ablation and pacing: long term follow up. Heart, 82(4):494-498.
Acquati F, Hammer R, Ercoli B, Mooser V, Tao R, Rönicke V, Michalich A, Chiesa G, Taramelli R, Hobbs HH, Müller HJ. 1999. Transgenic mice expressing a human apolipoprotein[a] allele. J Lipid Res, 40(6):994-1006.
Tibiletti MG, Furlan D, Taborelli M, Facco C, Riva C, Franchi M, Cossu A, Trubia M, Taramelli R, Capella C. 1999. Microsatellite instability in endometrial cancer: relation to histological subtypes. Gynecol Oncol., 73(2):247-252.
di Iasio MG, Calin G, Tibiletti MG, Vorechovsky I, Benediktsson KP, Taramelli R, Barbanti-Brodano G, Negrini M. 1999. Refinement of the LOH region 1 at 11q23.1 deleted in human breast carcinomas and sublocalization of 11 expressed sequence tags within the refined region. Oncogene, 18(8):1635-1638.