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Pleiotropic modes of action in tumor cells of RNASET2, an evolutionary highly conserved extracellular RNase.

Lualdi M, Pedrini E, Rea K, Monti L, Scaldaferri D, Gariboldi M, Camporeale A, Ghia P, Monti E, Tomassetti A, Acquati F, Taramelli R - Oncotarget (2015)

Bottom Line: Indeed, RNASET2 expression levels were consistently found to increase following stress induction.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Theoretical and Applied Sciences, Università degli Studi dell'Insubria, Varese, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

RNASET2 secretion is required for in vivo tumor suppressionHey3Met2 cells clones stably transfected with pcDNA3 vector (Ctrl), wild-type (WT) and KDEL-RNASET2-expressing vectors were inoculated in nude mice and tumor growth was evaluated every 2-3 days. A) Western blot analysis on cell extracts and cell culture supernatants from single clones, showing complete inhibition of secretion of KDEL-modified RNASET2 protein. IC: intracellular; EC: extracellular. B) In vivo tumor growth kinetics from three clones for each experimental group.
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Figure 1: RNASET2 secretion is required for in vivo tumor suppressionHey3Met2 cells clones stably transfected with pcDNA3 vector (Ctrl), wild-type (WT) and KDEL-RNASET2-expressing vectors were inoculated in nude mice and tumor growth was evaluated every 2-3 days. A) Western blot analysis on cell extracts and cell culture supernatants from single clones, showing complete inhibition of secretion of KDEL-modified RNASET2 protein. IC: intracellular; EC: extracellular. B) In vivo tumor growth kinetics from three clones for each experimental group.

Mentions: As shown in Figure 1A, the KDEL-modified RNASET2 protein was easily detected in Hey3Met2 cell extracts but not in cell culture supernatants following stable transfection, confirming that it cannot be secreted. Strikingly, unlike wild-type RNASET2 cDNA-transfected cells, Hey3Met2 cells overexpressing KDEL-modified RNASET2 were not suppressed in their tumorigenic potential, giving rise to large tumors whose size was similar to that observed in control Hey3Met2 cells, which do not express RNASET2 (Figure 1B).


Pleiotropic modes of action in tumor cells of RNASET2, an evolutionary highly conserved extracellular RNase.

Lualdi M, Pedrini E, Rea K, Monti L, Scaldaferri D, Gariboldi M, Camporeale A, Ghia P, Monti E, Tomassetti A, Acquati F, Taramelli R - Oncotarget (2015)

RNASET2 secretion is required for in vivo tumor suppressionHey3Met2 cells clones stably transfected with pcDNA3 vector (Ctrl), wild-type (WT) and KDEL-RNASET2-expressing vectors were inoculated in nude mice and tumor growth was evaluated every 2-3 days. A) Western blot analysis on cell extracts and cell culture supernatants from single clones, showing complete inhibition of secretion of KDEL-modified RNASET2 protein. IC: intracellular; EC: extracellular. B) In vivo tumor growth kinetics from three clones for each experimental group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480721&req=5

Figure 1: RNASET2 secretion is required for in vivo tumor suppressionHey3Met2 cells clones stably transfected with pcDNA3 vector (Ctrl), wild-type (WT) and KDEL-RNASET2-expressing vectors were inoculated in nude mice and tumor growth was evaluated every 2-3 days. A) Western blot analysis on cell extracts and cell culture supernatants from single clones, showing complete inhibition of secretion of KDEL-modified RNASET2 protein. IC: intracellular; EC: extracellular. B) In vivo tumor growth kinetics from three clones for each experimental group.
Mentions: As shown in Figure 1A, the KDEL-modified RNASET2 protein was easily detected in Hey3Met2 cell extracts but not in cell culture supernatants following stable transfection, confirming that it cannot be secreted. Strikingly, unlike wild-type RNASET2 cDNA-transfected cells, Hey3Met2 cells overexpressing KDEL-modified RNASET2 were not suppressed in their tumorigenic potential, giving rise to large tumors whose size was similar to that observed in control Hey3Met2 cells, which do not express RNASET2 (Figure 1B).

Bottom Line: Indeed, RNASET2 expression levels were consistently found to increase following stress induction.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Theoretical and Applied Sciences, Università degli Studi dell'Insubria, Varese, Italy.

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.

No MeSH data available.


Related in: MedlinePlus