Abstract
RNASET2 is an extracellular ribonuclease endowed with a marked antitumorigenic role in several carcinomas, independent from its catalytic activity. Besides its antitumorigenic role by the recruitment to the tumor mass of immune cells from the monocyte/macrophage lineage, RNASET2 is induced by cellular stress and involved in actin cytoskeleton remodeling affecting cell interactions with the extracellular matrix (ECM). Here, we aimed to investigate the effects of RNASET2 expression modulation on cell phenotype and behavior in epithelial ovarian cancer (EOC) cellular models. In silico analysis on two publicly available datasets of gene expression from EOC patients (n = 392) indicated that increased RNASET2 transcript levels are associated with longer overall survival. In EOC biopsies (n = 101), analyzed by immunohistochemistry, RNASET2 was found heterogeneously expressed among tumors with different clinical–pathological characteristics and, in some cases, its expression localized to tumor-associated ECM. By characterizing in vitro two models of EOC cells in which RNASET2 was silenced or overexpressed, we report that RNASET2 expression negatively affects growth capability by conferring a peculiar cell phenotype upon the interaction of EOC cells with the ECM, resulting in decreased src activation. Altogether, these data suggest that drugs targeting activated src might represent a therapeutic approach for RNASET2-expressing EOCs.
Highlights
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-related deaths among women, and the leading cause of death from gynecological cancer
In keeping with experimental data suggesting its role as a tumor suppressor [7,12,13], RNASET2 expression has been so far associated to less aggressive phenotypes in several cancer models, including ovarian cancer [7,8,9,13,14]
We provide the first direct evidence that RNASET2 expression, at least at the transcript level, which characterizes an epithelial ovarian cancer (EOC) subgroup with better outcome
Summary
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-related deaths among women, and the leading cause of death from gynecological cancer. High grade EOCs are frequently diagnosed when the patients present peritoneal solid primary and secondary lesions associated, in ~40% of the patients, to malignant ascites rich of tumor multicellular aggregates (MCAs). These MCAs overcome anoikis, persist as ascites, and attach on the abdominal peritoneum or omentum, suggesting that the attachment through integrins of cancer cells onto the mesothelial cells covering the basement membrane is an important key step in EOC dissemination [3]. Human RNASET2, a ribonuclease that belongs to the T2 family, has recently emerged as an appealing new player in oncology displaying marked tumorigenic and metastatic suppressor properties. The RNASET2 protein is usually detected in three isoforms: a 0 full length0 form of
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