Regulation of onco and tumor suppressor MiRNAs by mTORC1 inhibitor PRP-1 in human chondrosarcoma

Abstract

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. This study aimed to reveal the comparative analysis of miRNAs and their targets in human JJ012 chondrosarcoma cell line between control and experimental samples, treated with mTORC1 inhibitor, cytostatic antiproliferative proline-rich polypeptide (PRP-1). Examination of tumor-specific microRNA expression profiles has revealed widespread deregulation of these molecules in diverse cancers. It was reported that microRNAs can function as novel biomarkers for disease diagnostics and therapy, as well as a novel class of oncogenes and tumor suppressor genes. mTORC 1 inhibitor PRP-1 caused significant upregulation of tumor suppressors, such as miR20a, miR125b, and miR192; and downregulation of onco miRNAs, miR509-3p, miR589, miR490-3p, miR 550 in human chondrosarcoma JJ012 cell line.

Effect of cytostatic proline rich polypeptide-1 on tumor suppressors of inflammation pathway signaling in chondrosarcoma

“…The upregulation of SOCS3, TET1 and TET2 expression in a dose-dependent manner by PRP-1 further demonstrates the ability of this cytokine peptide to upregulate tumor suppressor genes in general (8)(9)(10). Even though PRP-1 did not exert any effect on tumor suppressors or oncoproteins of the Hippo or Hedgehog signaling pathways, there was an important conclusion to consider: The inhibition of tumor suppressors by PRP-1 depends on the pathway these tumor suppressors represent or are involved in.…”

“…The effect of the mammalian target of rapamycin complex 1 (mTORC1) inhibitor and anti-proliferative immunomodulator, proline-rich polypeptide 1 (PRP-1) (3-7), on the expression of cytokines, tumor suppressors SOCS3, TET1/2 and oncoproteins of inflammatory oncogenic pathways, including the Hedgehog and Hippo pathways, was also investigated. PRP-1 is a powerful upregulator of tumor suppressor microRNAs (miRNAs) and proteins, and a downregulator of oncoproteins, as reported in previous publications from our laboratory (8)(9)(10). Ten eleven translocation (TET) enzymes, a family of α-ketoglutarate (α-KG)-dependent dioxygenases, catalyse the oxidative reactions of 5-methylcytosine (5mC) to promote the DNA demethylation process.…”

“…Understanding the differences in their expression patterns between the normal and malignant states, and the signaling pathways that lead to these differences, require further investigation as important targets for future therapeutic interventions. Metastatic chondrosarcoma does not respond to conventional therapies and the search for new therapeutic approaches is urgent (2)(3)(4)(5)(6)(7)(8)(9)(10)36,46). The ability of PRP-1 as an antiproliferative agent to restore the expression of anti-inflammatory cytokines with tumor suppressor function proves the importance of this neuropeptide for future clinical consideration.…”

Epigenetic control of cancer by neuropeptides

“…Cytostatic PRP-1 manifests its antiproliferative effect via cell cycle regulation in cancer (10), as well as by its unique ability to upregulate tumor suppressor proteins (26) and micro RNA (miR) tumor suppressors (miR20a, miR125b and miR192) while causing downregulation of onco-miRs (miR509-3p, miR589, miR490-3p and miR 550) in the human chondrosarcoma cell line, JJ012 (27), demonstrating the possibility for future therapeutic interventions.…”

MicroRNAs as potential target in human bone and soft tissue sarcoma therapeutics

“…The first significant study of miRNAs in chondrosarcoma tissue samples and cell lines revealed downregulation of let-7a, miR-100, miR-136, miR-222, miR-335, and miR-376a compared to normal chondrocytes (Yoshitaka et al, 2013; Nugent, 2014). Another recent study shows that overexpressing proline-rich polypeptide (PRP-1) inhibited mTORC1, which resulted in upregulation of certain tumor suppressor miRNAs (miR-125b, miR-192) and downregulation of oncomiRs (miR-550, miR-589, miR-490-3p) (Galoian et al, 2014). Similarly, another study demonstrated that overexpression of miR-518b decreased the expression of Bcl-2, which is an anti-apoptotic that led to increased expression of Bax, a pro-apoptotic in human chondrosarcoma cell lines (Liang et al, 2014).…”