Title: Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis
Authors: ACQUATI FrancescoLUALDI MartaBERTILACCIO SabrinaMONTI LauraTURCONI GiovannaFABBRI MarcoGRIMALDI AnnalisaANSELMO AchilleINFORZATO AntonioCOLLOTTA AngeloCIMETTI LauraRIVA CristinaGRIBALDO LauraGHIA PaoloTARAMELLI Roberto
Citation: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA vol. 110 no. 20 p. 8140–8145
Publisher: NATL ACAD SCIENCES
Publication Year: 2013
JRC N°: JRC82090
ISSN: 0027-8424
URI: www.pnas.org/cgi/doi/10.1073/pnas.1222079110
http://publications.jrc.ec.europa.eu/repository/handle/JRC82090
DOI: 10.1073/pnas.1222079110
Type: Articles in periodicals and books
Abstract: 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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