-:ology Research, Vol. 17, pp. 69-74:-_~ted in the USA. All rights reserved.= :?"right © 2008 Cognizant Comm. Corp.

0965-0407/08 $90.00 + .00E-ISSN 1555-3906

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RNASET2 as a Tumor Antagonizing Gene in a Melanoma Cancer Model

Laura Monti,* Monica Rudolfo,t Girieca Lo Russo,+ Douglas Noonan,:j: Francesco Acquati,*and Roberto Taramelli *

*Department of Biotechnology and Molecular Sciences, University of Insubria, Varese, ItalytUnit of Immunotherapy of Human Tumors, Department of Experimental Oncology, Fondazione Istituto di Ricovero e Cura a

Carattere Scientifico, Istituto Nazionale per 10Studio e la Cura dei Tumori, Milano, ItalytDepartment of Biological and Clinical Sciences, University of Insubria, Varese, Italy

The RNASET2 gene, mapped in 6q27, was previously found to exert control of tumorigenesis in an ovariancancer system. We present here results indicating a similar control in a melanoma cancer model. Thus, thisgene is most likely involved in a common general pathway of tumorigenesis. Moreover, its antitumorigenicactivity is manifested in vivo but not in vitro, suggesting that this gene belongs to the growing category oftumor antagonizing/malignancy suppressor genes. A possible role of RNASET2 in the activation of a senes-cence program, whose responsible locus was mapped in the same chromosomal 6q27 region, seems to beinconsistent with our data.

In recent years, a solid body of epidemiological evi-dence has indicated that the peritelomeric region of hu-man chromosome 6, namely 6q27 , harbors one or moretumor suppressor genes involved in a wide range oftumor types (1-3). Despite intense efforts by severalgroups, including ours, no genes belonging to this classof tumor suppressors have been unequivocally isolatedand characterized so far in this region.

Our group has recently isolated and partially charac-terized a gene from 6q27 called RNASET2 (4). This geneis the first mammalian member of the widespread familyof T2 RNAses to be described. Proteins belonging to theRNAse T2 family (EC 3.1.27.1) are present in all philaand are endorsed with disparate functions: for instance,in some microorganisms and plants T2 RNAses can me-diate phosphate uptake by digesting extracellular RNAs(5), whereas in self-incompatible plants, specific T2RNAses prevent self-fertilization by inhibiting the growthof the pollen tube (6). In still other species, T2 RNAseshave been described to provide host protection againstpathogens or to trigger cellular senescence (7,8). Al-though involved in apparently different biological pro-cesses, the most basic and relevant features of RNAseT2proteins are their localization in the extracellular milieu(where RNAs are conventionally thought to be unavail-

able) and their ability to control cell growth. Therefore,a functional link between these two features has beenenvisioned, suggesting that RNAses belonging to thisfamily, besides intracellular RNA digestion, are en-dorsed with novel biological functions that are per-formed outside the cell.

Among these biological functions, the well-describedcontrol of cellular growth mediated by T2 RNAses isparticularly attracting from the oncological point ofview. Indeed, RNASET2 was found by our group to behypoexpressed or absent at the transcript level in severalprimary ovarian tumors and ovarian cell lines (9). More-over, we reported a clear inhibition of tumor growth fol-lowing inoculation in nude mice of RNASET2-overex-pressing cells from the Hey2Met3 ovarian cancer cellline (10). Despite such a strong effect in vivo, theRNASET2-transfected cells did not show any changewhen cancer-related parameters were assayed in vitro.The behavior of RNASET2 is thus reminiscent of thatdescribed for the so-called "tumor-antagonizing" or"malignancy suppressor genes," which are characterizedby an asymmetric oncosuppressive activity (namely, theability to suppress tumorigenicity in vivo without affect-ing growth in vitro) (11-13), and whose occurrence inthe human genome is estimated to be more frequent thanpredicted, although very few examples are available todate.

Addresscorrespondenceto FrancescoAcquati,Departmentof BiotechnologyandMolecularSciences,viaJH Dunant3, 21100 Varese,Italy.Tel:+39-0332-421512; Fax:+39-0332-421500; E-mail:francesco.acquati@uninsubria.it

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