Potential Anti-Metastatic Role of the Novel miR-CT3 in Tumor Angiogenesis and Osteosarcoma Invasion

Abstract

Osteosarcoma (OS) is the most common primary bone tumor mainly occurring in young adults and derived from primitive bone-forming mesenchyme. OS develops in an intricate tumor microenvironment (TME) where cellular function regulated by microRNAs (miRNAs) may affect communication between OS cells and the surrounding TME. Therefore, miRNAs are considered potential therapeutic targets in cancer and one of the goals of research is to accurately define a specific signature of a miRNAs, which could reflect the phenotype of a particular tumor, such as OS. Through NGS approach, we previously found a specific molecular profile of miRNAs in OS and discovered 8 novel miRNAs. Among these, we deepen our knowledge on the fifth candidate renamed now miR-CT3. MiR-CT3 expression was low in OS cells when compared with human primary osteoblasts and healthy bone. Through TargetScan, VEGF-A was predicted as a potential biological target of miR-CT3 and luciferase assay confirmed it. We showed that enforced expression of miR-CT3 in two OS cell lines, SAOS-2 and MG-63, reduced expression of VEGF-A mRNA and protein, inhibiting tumor angiogenesis. Enforced expression of miR-CT3 also reduced OS cell migration and invasion as confirmed by soft agar colony formation assay. Interestingly, we found that miR-CT3 behaves inducing the activation of p38 MAP kinase pathway and modulating the epithelial-mesenchymal transition (EMT) proteins, in particular reducing Vimentin expression. Overall, our study highlights the novel role of miR-CT3 in regulating tumor angiogenesis and progression in OS cells, linking also to the modulation of EMT proteins.

Three‐dimensional (3D) polylactic acid gradient scaffold to study the behavior of osteosarcoma cells under dynamic conditions

“…Osteosarcoma (OS) is the most common primary malignant tumor of bone in children and adolescents, it poses a significant clinical challenge with limited treatment options and poor prognosis. [1][2][3][4] Novel therapies to slow the progression and eradicate the disease [5][6][7][8][9] and the development of novel predictive culture systems resembling the native three-dimensional (3D) tumor microenvironment are required. 10 The development of advanced scaffold systems that mimic the native extracellular matrix (ECM) and provide a suitable microenvironment for tumor modeling and therapeutic evaluation is crucial for enhancing our understanding and improving treatment outcomes.…”

“…Osteosarcoma (OS) is the most common primary malignant tumor of bone in children and adolescents, it poses a significant clinical challenge with limited treatment options and poor prognosis 1–4 . Novel therapies to slow the progression and eradicate the disease 5–9 and the development of novel predictive culture systems resembling the native three‐dimensional (3D) tumor microenvironment are required 10…”

Role of MicroRNAs in Cancer Development and Treatment

“…Moreover, they confirmed that VEGF-A is a directed target of miR-CT3 and showed that its enforced expression in SAOS-2 and MG-63 cells reduced not only the expression of VEGF-A mRNA and protein, but also inhibited OS cell migration and invasion. In addition, they reported that miR-CT3 activated the p38 MAP kinase pathway and reduced the expression of EMT players such as vimentin [ 7 ].…”