Role of Activator Protein-1 Complex on the Phenotype of Human Osteosarcomas Generated from Mesenchymal Stem Cells

Gambera, Stefano; Abarrategi, Ander; Rodríguez-Milla, Miguel Ángel; Mulero, Francisca; Menéndez, Sofía T.; Navarro, Samuel; García‐Castro, Javier

doi:10.1002/stem.2869

Cited by 15 publications

(12 citation statements)

References 48 publications

(54 reference statements)

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“…The results showed that miR-708-5p was downregulated in five OS cell lines (MG63, HOS, NY, SaOS-2, and Hu09) compared with hMSCs. Tumor-initiating cells of OS may be derived from mesenchymal stem cells in given bone circumstances (37). The differential expression of miR-708-5p in OS cells and hMSCs prompted us to consider whether it is involved in the occurrence and development of OS.…”

Section: Discussionmentioning

confidence: 99%

The microRNA‑708‑5p/ZEB1/EMT axis mediates the metastatic potential of osteosarcoma

et al. 2019

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MicroRNA-708-5p (miR-708-5p) and epithelialto-mesenchymal transition (EMT) have been widely identified to contribute to the pathogenesis and progression of multiple cancers. However, the connection between miR-708-5p and EMT has not been sufficiently clarified. Therefore, our research aimed to investigate the impact of miR-708-5p on EMT and the metastasis of osteosarcoma (OS). We first analyzed the differentially expressed microRNAs (DEmiRNAs) from the GSE70367 dataset. We found that the expression of miR-708-5p was lower in OS cells. Overexpression of miR-708-5p was able to impair the migration and invasion of OS cells. Moreover, miR-708-5p inhibited EMT of OS cells MG63 and SaOS-2, wherein E-cadherin was increased, and N-cadherin, vimentin, and Snail were decreased. Semaphorin 4C (SEMA4C), mitogen-activated protein kinase kinase kinase 3 (MAP3K3), and zinc finger E-box-binding homeobox 1 (ZEB1) were predicted as target genes of miR-708-5p by bioinformatics method. Only ZEB1, one of the EMT-inducing transcription factors, was validated as the direct target gene of miR-708-5p in OS cells through dual-luciferase reporter assay and Western blot analysis. Knockdown of ZEB1 was found to inhibit the metastasis of MG63 and SaOS-2 cells, whereas ZEB1 overexpression promoted their metastasis. In summary, miR-708-5p impaired the metastasis and EMT of OS, which was found to be mediated by inhibition of ZEB1.

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Section: Discussionmentioning

confidence: 99%

The microRNA‑708‑5p/ZEB1/EMT axis mediates the metastatic potential of osteosarcoma

et al. 2019

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“…126 Another study reported that 3H transformed hMSCs (overexpression of hTERT, p53, and pRB degradation) manipulated to overexpress c-JUN and c-JUN/c-FOS developed into fibroblastic and pleomorphic osteoblastic osteosarcomas, respectively. 127 Combined overexpression of the liposarcoma diagnostic markers, MDM2 and CDK4, increased human 2H transformed BM-MSCs (overexpression of hTERT, p53 degradation) proliferation, migration, and inhibited adipogenic differentiation potential in vitro. However, MDM2 and CDK4 overexpression in these MSCs only led to tumor growth in vivo and the formation of dedifferentiated liposarcoma when combined with three additional oncogenic hits (c-Myc stabilization, RB inactivation, and overexpression of H-RAS V12 ).…”

Section: Mesenchymal Stem Cells As the Putative Origin Of Sarcomasmentioning

confidence: 99%

Molecular mechanisms underpinning sarcomas and implications for current and future therapy

Damerell

Pepper

Prince

2021

Sig Transduct Target Ther

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Sarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

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“…Positive for APS and bone sialoprotein (BSP) upregulation [98] Not tested/shown Not tested/shown UE6E7T-2 (same parental cells as UE6E7-16) Not tested/shown Tested by ABS in 2D culture; negative under employed conditions [99] Not tested/shown imhMSCs Positive for VKS and upregulation of osteogenesis-related genes [18] Weak positivity for ABS and with weak upregulation of chondrogenesis-related genes (similarly to primary parental cells); tested in pellet culture [18] Positive for OROS and PPARγ upregulation [18] 3 Hits hMPC Positive for ARS [102,103], APS [101,102] and Runx2 upregulation [102] Positive for ABS [102,103] and TBS [101] in pellet culture, but reduced compared with primary MSCs…”

Section: Y201mentioning

confidence: 99%

“…Positive for OROS [101][102][103], but reduced compared with primary MSCs UE7T-13 (same parental cells as UE6E7-16)…”

Section: Y201mentioning

confidence: 99%

Usefulness of Mesenchymal Cell Lines for Bone and Cartilage Regeneration Research

Piñeiro-Ramil

Sanjurjo‐Rodríguez

Castro-Viñuelas

et al. 2019

IJMS

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The unavailability of sufficient numbers of human primary cells is a major roadblock for in vitro repair of bone and/or cartilage, and for performing disease modelling experiments. Immortalized mesenchymal stromal cells (iMSCs) may be employed as a research tool for avoiding these problems. The purpose of this review was to revise the available literature on the characteristics of the iMSC lines, paying special attention to the maintenance of the phenotype of the primary cells from which they were derived, and whether they are effectively useful for in vitro disease modeling and cell therapy purposes. This review was performed by searching on Web of Science, Scopus, and PubMed databases from 1 January 2015 to 30 September 2019. The keywords used were ALL = (mesenchymal AND ("cell line" OR immortal*) AND (cartilage OR chondrogenesis OR bone OR osteogenesis) AND human). Only original research studies in which a human iMSC line was employed for osteogenesis or chondrogenesis experiments were included. After describing the success of the immortalization protocol, we focused on the iMSCs maintenance of the parental phenotype and multipotency. According to the literature revised, it seems that the maintenance of these characteristics is not guaranteed by immortalization, and that careful selection and validation of clones with particular characteristics is necessary for taking advantage of the full potential of iMSC to be employed in bone and cartilage-related research.

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Role of Activator Protein-1 Complex on the Phenotype of Human Osteosarcomas Generated from Mesenchymal Stem Cells

Cited by 15 publications

References 48 publications

The microRNA‑708‑5p/ZEB1/EMT axis mediates the metastatic potential of osteosarcoma

The microRNA‑708‑5p/ZEB1/EMT axis mediates the metastatic potential of osteosarcoma

Molecular mechanisms underpinning sarcomas and implications for current and future therapy

Usefulness of Mesenchymal Cell Lines for Bone and Cartilage Regeneration Research

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