Molecular signature induced by RNASET2, a tumor antagonizing gene, in ovarian cancer cells

Acquati, Francesco; Monti, Laura; Lualdi, Marta; Fabbri, Marco; Sacco, Maria Grazia; Gribaldo, Laura; Taramelli, Roberto

doi:10.18632/oncotarget.274

Cited by 20 publications

(12 citation statements)

References 41 publications

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“…Therefore, although targeting of RNASET2 to P-bodies might suggest a rather general role in stress-induced RNA processing for this RNase, the results of this study suggest the occurrence of a sort of selectivity in target selection by this protein, although the mechanism ruling such putative selectivity are largely unknown. Our results thus, further confirm that the effects of RNASET2 on the cell transcriptome are more complex than expected, as already observed in previous investigations on the catalytically-dead RNASET2 protein (26).…”

Section: Discussionsupporting

confidence: 92%

“…Contrary to our expectations, a great proportion of transcripts (both miRNAs and mRNAs) turned out to be downregulated rather than upregulated in the absence of RNASET2, thus, suggesting that the mechanism(s) by which this ribonuclease affects the expression level of several intracellular transcripts might not involve a direct cleavage of target RNAs. Of note, in a previous report microarray-based gene expression profiling of the Hey3Met2 ovarian cancer cell line showed that overexpression of a catalytically-dead RNASET2 protein could nevertheless affect the cell transcriptome significantly, suggesting that this protein can affect the cellular gene expression profile independently of its ribonucleolytic activity (26). These data are in keeping with several recent reports showing that proteins belonging to the T2 family members can affect several biological processes in a catalytically-independent manner (22).…”

Section: Discussionsupporting

confidence: 85%

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RNASET2 silencing affects miRNAs and target gene expression pattern in a human ovarian cancer cell model

Turconi

Scaldaferri

Fabbri

et al. 2016

International Journal of Oncology

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Ribonucleases (RNases) are hydrolytic enzymes endowed with the ability to either process or degrade ribonucleic acids. Among the many biological functions assigned to RNases, a growing attention has been recently devoted to the control of cancer growth, in the attempt to bring novel therapeutic approaches to clinical oncology. Indeed, several enzymes belonging to different ribonuclease families have been reported in the last decade to display a marked oncosuppressive activity in a wide range of experimental models. The human RNASET2 gene, the only member of the highly conserved T2/Rh/S family of endoribonucleolytic enzymes described in our species, has been shown to display oncosuppressive roles in both in vitro and in vivo models representing several human malignancies. In the present study, we extend previous findings obtained in ovarian cancer models to shed further light on the cell-autonomous roles played by this gene in the context of its oncosuppresive role and to show that RNASET2 silencing can significantly affect the transcriptional output in one of the most thoroughly investigated human ovarian cancer cell lines. Moreover, we report for the first time that RNASET2-mediated changes in the cell transcriptome are in part mediated by its apparent ability to affect the cell's microRNA expression pattern.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 85%

RNASET2 silencing affects miRNAs and target gene expression pattern in a human ovarian cancer cell model

Turconi

Scaldaferri

Fabbri

et al. 2016

International Journal of Oncology

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“…Our research group has recently contributed to this issue by investigating the role of the human RNASET2 gene (10)(11)(12)(13)(14)(15). The latter codes for an extracellular RNase expressed in several tissues, including the ovary and tubal structures, and is highly conserved among phyla from viruses to humans, implying a crucial, evolutionary conserved function (16).…”

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confidence: 99%

Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis

Acquati¹,

Lualdi²,

Bertilaccio³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In recent years, the role played by the stromal microenvironment has been given growing attention in order to achieve a full understanding of cancer initiation and progression. Because cancer is a tissue-based disease, the integrity of tissue architecture is a major constraint toward cancer growth. Indeed, a large contribution of the natural resistance to cancer stems from stromal microenvironment components, the dysregulation of which can facilitate cancer occurrence. For instance, recent experimental evidence has highlighted the involvement of stromal cells in ovarian carcinogenesis, as epitomized by ovarian xenografts obtained by a double KO of the murine Dicer and Pten genes. Likewise, we reported the role of an ancient extracellular RNase, called Ribonuclease T2 (RNASET2), within the ovarian stromal microenvironment. Indeed, hyperexpression of RNASET2 is able to control tumorigenesis by recruiting macrophages (mostly of the anticancer M1 subtype) at the tumor sites. We present biological data obtained by RNASET2 silencing in the poorly tumorigenetic and highly RNASET2-expressing human OVCAR3 cell line. RNASET2 knockdown was shown to stimulate in vivo tumor growth early after microinjection of OVCAR3 cells in nude mice. Moreover, we have investigated by molecular profiling the in vivo expression signature of human and mouse cell xenografts and disclosed the activation of pathways related to activation of the innate immune response and modulation of ECM components. Finally, we provide evidence for a role of RNASET2 in triggering an in vitro chemotactic response in macrophages. These results further highlight the critical role played by the microenvironment in RNASET2-mediated ovarian tumor suppression, which could eventually contribute to better clarify the pathogenesis of this disease.

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“…Human RNASET2 is a glycoprotein encoded by the RNASET2 gene which is located on chromosome 6 (6q27) and demonstrated to be a tumor suppressor gene [16-20]. RNASET2 is the only member of the Rh/T2/S family of acidic hydrolases in humans [21] and shares 34% identity and 52% similarity with ACTIBIND (a fungal RNase T2).…”

Section: Introductionmentioning

confidence: 99%

Human RNASET2 derivatives as potential anti-angiogenic agents: actin binding sequence identification and characterization

et al. 2014

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Human RNASET2 (hRNASET2) has been demonstrated to exert antiangiogenic and antitumorigenic effects independent of its ribonuclease capacity. We suggested that RNASET2 exerts its antiangiogenic and antitumorigenic activities via binding to actin and consequently inhibits cell motility. We focused herein on the identification of the actin binding site of hRNASET2 using defined sequences encountered within the whole hRNASET2 protein. For that purpose we designed 29 different hRNASET2-derived peptides. The 29 peptides were examined for their ability to bind immobilized actin. Two selected peptides-A103-Q159 consisting of 57 amino acids and peptide K108-K133 consisting of 26 amino acids were demonstrated to have the highest actin binding ability and concomitantly the most potent anti-angiogenic activity.Further analyses on the putative mechanisms associated with angiogenesis inhibition exerted by peptide K108-K133 involved its location during treatment within the HUVE cells. Peptide K108-K133 readily penetrates the cell membrane within 10 min of incubation. In addition, supplementation with angiogenin delays the entrance of peptide K108-K133 to the cell suggesting competition on the same cell internalization route. The peptide was demonstrated to co-localize with angiogenin, suggesting that both molecules bind analogous cellular epitopes, similar to our previously reported data for ACTIBIND and trT2-50.

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Molecular signature induced by RNASET2, a tumor antagonizing gene, in ovarian cancer cells

Cited by 20 publications

References 41 publications

RNASET2 silencing affects miRNAs and target gene expression pattern in a human ovarian cancer cell model

RNASET2 silencing affects miRNAs and target gene expression pattern in a human ovarian cancer cell model

Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis

Human RNASET2 derivatives as potential anti-angiogenic agents: actin binding sequence identification and characterization

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