RNASET2 As a Tumor Antagonizing Gene in a Melanoma Cancer Model

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, Italy tUnit 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, Italy tDepartment 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 ovarian cancer system. We present here results indicating a similar control in a melanoma cancer model. Thus, this gene is most likely involved in a common general pathway of tumorigenesis. Moreover, its antitumorigenic activity is manifested in vivo but not in vitro, suggesting that this gene belongs to the growing category of tumor antagonizing/malignancy suppressor genes. A possible role of RNASET2 in the activation of a senescence program, whose responsible locus was mapped in the same chromosomal 6q27 region, seems to be inconsistent with our data.

able) and their ability to control cell growth. Therefore, a functional link between these two features has been In recent years, a solid body of epidemiological evi- envisioned, suggesting that RNAses belonging to this dence has indicated that the peritelomeric region of hu- family, besides intracellular RNA digestion, are en- man chromosome 6, namely 6q27 , harbors one or more dorsed with novel biological functions that are per- tumor suppressor genes involved in a wide range of formed outside the cell. tumor types (1-3). Despite intense efforts by several Among these biological functions, the well-described groups, including ours, no genes belonging to this class control of cellular growth mediated by T2 RNAses is of tumor suppressors have been unequivocally isolated particularly attracting from the oncological point of and characterized so far in this region. view. Indeed, RNASET2 was found by our group to be Our group has recently isolated and partially charac- hypoexpressed or absent at the transcript level in several terized a gene from 6q27 called RNASET2 (4). This gene primary ovarian tumors and ovarian cell lines (9). More- is the first mammalian member of the widespread family over, we reported a clear inhibition of tumor growth fol- of T2 RNAses to be described. Proteins belonging to the lowing inoculation in nude mice of RNASET2-overex- RNAse T2 family (EC 3.1.27.1) are present in all phila pressing cells from the Hey2Met3 ovarian cancer cell and are endorsed with disparate functions: for instance, line (10). Despite such a strong effect in vivo, the in some microorganisms and plants T2 RNAses can me- RNASET2-transfected cells did not show any change diate phosphate uptake by digesting extracellular RNAs when cancer-related parameters were assayed in vitro. (5), whereas in self-incompatible plants, specific T2 The behavior of RNASET2 is thus reminiscent of that RNAses prevent self-fertilization by inhibiting the growth described for the so-called "tumor-antagonizing" or of the pollen tube (6). In still other species, T2 RNAses "malignancy suppressor genes," which are characterized have been described to provide host protection against by an asymmetric oncosuppressive activity (namely, the pathogens or to trigger cellular senescence (7,8). Al- ability to suppress tumorigenicity in vivo without affect- though involved in apparently different biological pro- ing growth in vitro) (11-13), and whose occurrence in cesses, the most basic and relevant features of RNAseT2 the human genome is estimated to be more frequent than proteins are their localization in the extracellular milieu predicted, although very few examples are available to (where RNAs are conventionally thought to be unavail- date.

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