Abstract
Osteosarcoma (OS) is a malignant bone cancer with severe chromosomal abnormalities and genetic aberrations. Our previous work reported the dedifferentiation of OS, which is related to poor prognosis. However, the molecular mechanism that regulates OS dedifferentiation is still a subject of exploration. Emerging evidence has suggested that microRNAs (miRNAs) are associated with the pathogenesis of OS and could potentially be developed for use as diagnostic biomarkers and therapeutic strategies. In the present study, we intended to illustrate the role of miR-34a in the dedifferentiation of OS. Upregulation of miR-34a was observed while OS cells were induced into stem-like phenotype. Notably, inhibition of miR-34a could promote the reprogramming transition of OS. Further exploration on the downstream network of miR-34a identified that blocking plasminogen activator inhibitor-1 (PAI-1) expression could restrain OS dedifferentiation into cancer stem-like cells by downregulating SRY-related-HMG box (Sox) 2. We also showed that Sox2 overexpression rescued the suppression phenotype driven by PAI-1 inhibition. Conversely, PAI-1 inhibitor (PAI-039) could suppress the upregulation of Sox2 expression caused by miR-34a inhibition. Be applying bone extracellular matrix (BEM)-OS models, we demonstrated the phenotypic heterogeneity of OS cells, consistent with a strong concordance between PAI-1 and Sox2 expression levels. Taken together, our findings proved miR-34a to be a bona fide suppressor involved in the regulation of OS dedifferentiation. Targeting miR-34a or its direct target PAI-1 could offer new strategies for OS treatment.
Highlights
Osteosarcoma (OS) is the most common malignant primary bone tumor in childhood and adolescents, and represents the second highest cause of cancer-related death in children and young adults
During the process of dedifferentiation, multiple genes that were demonstrated to be pivotal in cancer stem cell properties were induced, including PDGFRB, NOTCH1, JAG1, HES1, and HEY1 of the Notch signaling, SNAI1 and SNAI217–20. qRT-PCR confirmed the results of microarray analysis (Supplementary Fig. S1f, g)
The vast majority of elongated cells located in the bone periosteum with plenty of nutrients and oxygen, while the rounded cells rested in cancellous bone and medullary cavity with poor medium permeation
Summary
Osteosarcoma (OS) is the most common malignant primary bone tumor in childhood and adolescents, and represents the second highest cause of cancer-related death in children and young adults. It features rapid development, local recurrence, strong metastatic ability and poor prognosis[1]. Tumor excision and adjuvant chemotherapy are the most commonly used treatments for OS2. Our previous study has revealed that abundant transforming growth factor β1 (TGFβ1) and hypoxic environment could induce OS cell toward a cancer stem cell (CSC) phenotype, which was termed as sarcosphere. Gene set enrichment analysis (GSEA) revealed that gene alterations during the process of dedifferentiation were closely correlated with chemoresistance and metastasis in OS patients[4]
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