PAI‐1, a target gene of miR‐143, regulates invasion and metastasis by upregulating MMP‐13 expression of human osteosarcoma

Abstract

Despite recent improvements in the therapy for osteosarcoma, 30–40% of osteosarcoma patients die of this disease, mainly due to its lung metastasis. We have previously reported that intravenous injection of miR‐143 significantly suppresses lung metastasis of human osteosarcoma cells (143B) in a mouse model. In this study, we examined the biological role and mechanism of miR‐143 in the metastasis of human osteosarcoma cells. We identified plasminogen activator inhibitor‐1 (PAI‐1) as a direct target gene of miR‐143. To determine the role of PAI‐1 in human osteosarcoma cells, siRNA was transfected into 143B cells for knockdown of PAI‐1 expression. An in vitro study showed that downregulation of PAI‐1 suppressed cell invasion activity, but not proliferation. Moreover, injection of PAI‐1 siRNA into a primary lesion in the osteosarcoma mouse model inhibited lung metastasis compared to control siRNA‐injected mice, without influencing the proliferative activity of the tumor cells. Subsequent examination using 143B cells revealed that knockdown of PAI‐1 expression resulted in downregulation of the expression and secretion of matrix metalloproteinase‐13 (MMP‐13), which is also a target gene of miR‐143 and a proteolytic enzyme that regulates tumor‐induced osteolysis. Immunohistochemical analysis using clinical samples showed that higher miR‐143 expressing cases showed poor expression of PAI‐1 in the primary tumor cells. All such cases belonged to the lung metastasis‐negative group. Moreover, the frequency of lung metastasis‐positive cases was significantly higher in PAI‐1 and MMP‐13 double‐positive cases than in PAI‐1 or MMP‐13 single‐positive or double‐negative cases (P < 0.05). These results indicated that PAI‐1, a target gene of miR‐143, regulates invasion and lung metastasis via enhancement of MMP‐13 expression and secretion in human osteosarcoma cells, suggesting that these molecules could be potential therapeutic target genes for preventing lung metastasis in osteosarcoma patients.

Long noncoding RNA NEAT1 aggravates osteosarcoma carcinogenesis via regulating the microRNA-579/MMP13 axis

“…Previous studies showed that MMP13 could act as a tumor oncogene in OS progression [34][35][36]. Thus, in the present study, we detected whether MMP13 could act as a target of miR-579 in OS.…”

Pathological and therapeutic aspects of matrix metalloproteinases: Implications in osteosarcoma

“…They showed that knockdown of PAI‐1 expression suppressed cell invasion by downregulating the expression and secretion of MMP‐13. They also found that injection of PAI‐1 siRNA into a primary lesion in the OS mouse model inhibited lung metastasis . Relaxin‐2 (RLN2) is reported to be involved in migration, invasiveness and proliferation of OS cells mediated through S100A4/MMP‐9 signaling.…”

“…It is reported that MMP‐13 might be available metastasis‐prediction markers for OS. The expression of MMP‐13 is upregulated by stimulation of human OS cell lines with TGF‐β, during which MMP‐13 transcription was directly promoted by the transcriptional activator Cbfa1 (core binding factor 1) . Epidermal growth factor‐containing fibulin‐like ECM protein 1 (EFEMP1, also called fibulin‐3) is reported to be upregulated in OS.…”

Identification of potential prognostic markers for osteosarcoma by integrated analysis

“…Ma et al identi ed MMP-13 as the target gene of proteolytic enzyme that regulated tumor-induced osteolysis [28]. Hirahata and colleagues showed that high MMP13 expression was of great importance for the survival of OS cells [29]. Decorin (DCN), Procollagen C-proteinase enhancer protein (PCOLCE) and Runx2 were found to play a vital role in lung metastasis of OS [30,31].…”