Abstract
As widely recognized, tumor growth entails a close and complex cross-talk among cancer cells and the surrounding tumor microenvironment. We recently described the human RNASET2 gene as one key player of such microenvironmental cross-talk. Indeed, the protein encoded by this gene is an extracellular RNase which is able to control cancer growth in a non-cell autonomous mode by inducing a sustained recruitment of immune-competent cells belonging to the monocyte/macrophage lineage within a growing tumor mass. Here, we asked whether this oncosuppressor gene is sensitive to stress challenges and whether it can trigger cell-intrinsic processes as well. Indeed, RNASET2 expression levels were consistently found to increase following stress induction. Moreover, changes in RNASET2 expression levels turned out to affect several cancer-related parameters in vitro in an ovarian cancer cell line model. Of note, a remarkable rearrangement of the actin cytoskeleton organization, together with changes in cell adhesion and motility, emerged as putative mechanisms by which such cell-autonomous role could occur. Altogether, these biological features allow to put forward the hypothesis that the RNASET2 protein can act as a molecular barrier for limiting the damages and tissue remodeling events occurring during the earlier step of cell transformation.
Highlights
The human RNASET2 gene encodes a highly conserved and secreted ribonuclease which acts as a tumor suppressor in several cancer models [1,2,3,4,5,6]
In an ovarian cancer model, we recently found that such oncosuppressive role relies on RNASET2-mediated in vivo recruitment of cells from the monocyte/macrophage lineage in the tumor mass [5, 6]
Molecular correlates of RNASET2-associated biological responses were recently provided by our group following investigations in an ovarian cancer cell-based xenograft model, where in vivo gene expression profiling disclosed a significant RNASET2-dependent modulation of expression for gene categories related to immune response functions [6], strongly suggesting a role for RNASET2 as an alarmin-like molecule
Summary
The human RNASET2 gene encodes a highly conserved and secreted ribonuclease which acts as a tumor suppressor in several cancer models [1,2,3,4,5,6]. Molecular correlates of RNASET2-associated biological responses were recently provided by our group following investigations in an ovarian cancer cell-based xenograft model, where in vivo gene expression profiling disclosed a significant RNASET2-dependent modulation of expression for gene categories related to immune response functions [6], strongly suggesting a role for RNASET2 as an alarmin-like molecule. The latter represent endogenous danger-signaling molecules that are either passively secreted by necrotic cells or actively secreted by leukocytes or epithelial cells in order to signal the occurrence of tissue-damaging events, such as infectionmediated injury [10, 11]. The hypothesis of RNASET2 as an early determinant of tumorigenesis, coupled to its behaviour as a putative alarmin-like molecule, prompted us to investigate whether this gene could be involved in microenvironmental stress response, possibly acting as a sensor of cellular damage, as recently described for the Saccharomyces cerevisiae ortholog of RNASET2 (Rny1p), which plays an important role in the response to oxidative stress [12]
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