Human RNASET2: A Highly Pleiotropic and Evolutionary Conserved Tumor Suppressor Gene Involved in the Control of Ovarian Cancer Pathogenesis

Abstract

Ovarian cancer represents one of the most malignant gynecological cancers worldwide, with an overall 5-year survival rate, being locked in the 25–30% range in the last decade. Cancer immunotherapy is currently one of the most intensively investigated and promising therapeutic strategy and as such, is expected to provide in the incoming years significant benefits for ovarian cancer treatment as well. Here, we provide a detailed survey on the highly pleiotropic oncosuppressive roles played by the human RNASET2 gene, whose protein product has been consistently reported to establish a functional crosstalk between ovarian cancer cells and key cellular effectors of the innate immune system (the monocyte/macrophages lineage), which is in turn able to promote the recruitment to the cancer tissue of M1-polarized, antitumoral macrophages. This feature, coupled with the ability of T2 ribonucleases to negatively affect several cancer-related parameters in a cell-autonomous manner on a wide range of ovarian cancer experimental models, makes human RNASET2 a very promising candidate to develop a “multitasking” therapeutic approach for innovative future applications for ovarian cancer treatment.

Tumors Established in a Defective Immune Environment Reprogram the Oncogenic Signaling Pathways to Escalate Tumor Antigenicity

“…As shown in Figure 1c, an inconsistency of the DEPs in the CT26/SCID and CT26/BALB/c tumors was found. For example, PTEN [33], RBL1 [34], CDKN2AIP [35], RNASET2A [36], HINT1 [37], and PARP12 [38] are well-known tumor suppressors and were downregulated or absent in the CT26/SCID tumors (Table S1). The enriched signaling pathways involved in cell cycles, namely, PIP3-activated AKT signaling, mTOR signaling, WNT signaling, and MAPK activation, suggested that the manipulation of tumor growth was significantly changed in the NOD.SCID mice.…”

The Potential Role of the T2 Ribonucleases in TME-Based Cancer Therapy

“…Noteworthy, as already mentioned, T2 ribonucleases display an impressive degree of evolutionary conservation, suggesting a crucial and very ancient biological role for this class of enzymes [ 65 ]. Furthermore, a great bulk of experimental evidence has been gathered in the last decades to suggest a marked oncosuppressive activity of the human RNASET2 protein in both in vivo and in vitro experimental settings ( Figure 1 E) [ 85 ]. Noteworthy, negative control of cell growth, induction of apoptosis, and a marked remodeling of the cell cytoskeleton (all representing biological processes deeply involved in tumor suppression) were consistently reported to be modulated by several members of the T2 RNase family from evolutionarily distant species, ranging from Saccharomyces cerevisiae to Homo sapiens.…”