Metastatic
chondrosarcoma of mesenchymal origin is the second most common bone
malignancy and does not respond either to
chemotherapy or radiation; therefore, the search for new
therapies is relevant and urgent. We described recently that
tumor growth inhibiting
cytostatic proline-rich
polypeptide 1, (PRP-1) significantly upregulated
tumor suppressor
miRNAs, downregulated onco-
miRNAs in human
chondrosarcoma JJ012 cell line, compared to chondrocytes culture. In this study we hypothesized the existence and regulation of a functional marker in cancer stem cells, correlated to
peptides antiproliferative activity. Experimental results indicated that among significantly downregulated
miRNA after PRP-1treatment was
miRNAs 302c*. This
miRNA is a part of the cluster miR302‑367, which is stemness regulator in human embryonic stem cells and in certain
tumors, but is not expressed in adult hMSCs and normal tissues. PRP-1 had strong inhibitory effect on viability of
chondrosarcoma and multilineage induced multipotent adult cells (embryonic primitive cell type). Unlike
chondrosarcoma, in
glioblastoma, PRP-1 does not have any inhibitory activity on cell proliferation, because in
glioblastoma miR-302-367 cluster plays an opposite role, its expression is sufficient to suppress the stemness inducing properties. The observed correlation between the antiproliferative activity of PRP-1 and its action on downregulation of miR302c explains the
peptides opposite effects on the upregulation of proliferation of adult mesenchymal stem cells, and the inhibition of the proliferation of human bone
giant-cell tumor stromal cells, reported earlier. PRP-1 substantially downregulated the miR302c targets, the stemness markers Nanog, c-Myc and polycomb
protein Bmi-1. miR302c expression is induced by JMJD2-mediated H3K9me2 demethylase activity in its promoter region. JMJD2 was reported to be a positive regulator for Nanog. Our experimental results proved that PRP-1 strongly inhibited H3K9 activity comprised of a pool of JMJD1 and JMJD2. We conclude that inhibition of H3K9 activity by PRP-1 leads to downregulation of miR302c and its targets, defining the PRP-1 antiproliferative role.