Loss of miR-198 and -206 during primary tumor progression enables metastatic dissemination in human osteosarcoma

Abstract

The metastatic dissemination is a complex multistep process by which tumor cells from a primary site enter into the systemic circulation to finally spread at distant sites. Even if this mechanism is rare at the tumor level, it remains the major cause of Osteosarcoma-patients’ relapse and mortality. MicroRNAs (miRNAs) have recently been described as novel epigenetics’ genes’ expression regulators actively implicated in cancer progression and dissemination. The understanding of their implication in the metastatic spreading could help clinicians to improve the outcome of osteosarcoma. We established the miRNA’s expression-profile between primary bone-tumors (PTs), circulating tumor cells (CTCs) and lung metastatic (META) samples from in vivo mice xenograft models. Our results show that the expression level of the miR-198 and -206 was decreased in META samples, in which the expression of the metastasis-related receptor C-Met was up-regulated. Those expression variations were validated in osteosarcoma patient biopsies from matching primary tumors and lung metastasis. We validated in vitro the endogenous miRNAs inhibitory effects on both migration and invasion, as well as we confirmed by luciferase assays that the C-Met receptor is one of their bona-fide targets. The anti-metastatic effect of these miRNAs was also validated in vivo, as their direct injections into the tumors reduce the number of lung-metastases and prolongs the overall survival of the treated animals. All together, our results suggest the absence of the miR-198 and -206 as powerful predictive biomarkers of the tumor cell dissemination and the rationale of their potential therapeutic use in the treatment of Osteosarcoma.

Overexpression of miR‑206 in osteosarcoma and its associated molecular mechanisms as assessed through TCGA and GEO databases

“…miRNAs and their target genes represent potential novel therapeutic biomarkers for OS (33,34). Previous studies have reported downregulated miR-206 expression in OS cells (35)(36)(37)(38). However, miR-206 expression was demonstrated to be upregulated in human OS tissues in the present study.…”

miR-328-3p mediates the anti-tumor effect in osteosarcoma via directly targeting MMP-16

“…Besides, miR-1301 was reported to be an inhibitor of tumorigenesis in hepatocellular carcinoma cells [28]. In addition, there were some reports indicated that miRNAs could regulate the progression and developments of osteosarcoma (OS) [23, 29, 30]. In the previous report, we found that miR-328-3p was significantly decreased in the hepatocellular carcinoma (HCC) tissues, which was validated by gene microarray analysis [31].…”

“…MiRNAs are a type of evolutionarily conserved noncoding RNAs which are about 18–25 nt in length and negatively regulate the gene expression at the posttranscriptional level by directly inhibiting the target genes [22, 23]. The biological function and mechanism of miRNAs have been studied broadly.…”

Study on Targeting Relationship Between miR-320b and FGD5-AS1 and Its Effect on Biological Function of Osteosarcoma Cells

“… 3 It is reported that the 5-year survival rate of patients with osteosarcoma is about 70%. 4 Although our understanding of osteosarcoma has been improved with the deepening of research, there are still many patients with chemotherapy resistance and lung metastasis with a 5-year survival rate of less than 20% and an unfavorable prognosis. 5 , 6 And the molecular mechanisms underlying the development of carcinogenesis and metastasis are still unknown.…”