Exosomal transfer of miR-769-5p promotes osteosarcoma proliferation and metastasis by targeting DUSP16

Liu, Wanshun; Wang, Binyu; Duan, Ao; Shen, Kai; Zhang, Qi; Tang, Xiangming; Wei, Yongzhong; Tang, Jian; Zhang, Sheng

doi:10.1186/s12935-021-02257-4

Cited by 21 publications

(12 citation statements)

References 56 publications

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“…miR-769-5p suppressed cell proliferation, migration, and invasion targeting TGFBRI mRNA in non-small cell lung carcinoma [35]. Conversely, in osteosarcoma, it has been demonstrated to promote cell proliferation, invasion and metastasis by targeting the phosphatase DUSP16 [23].…”

Section: Discussionmentioning

confidence: 99%

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Restoration of WT1/miR-769-5p axis by HDAC1 inhibition promotes MMT reversal in mesenchymal-like mesothelial cells

et al. 2022

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Histone acetylation/deacetylation play an essential role in modifying chromatin structure and in regulating cell plasticity in eukaryotic cells. Therefore, histone deacetylase (HDAC) pharmacological inhibitors are promising tools in the therapy of fibrotic diseases and in cancer. Peritoneal fibrosis is a pathological process characterized by many cellular and molecular alterations, including the acquisition of invasive/pro-fibrotic abilities by mesothelial cells (MCs) through induction of mesothelial to mesenchymal transition (MMT). The aim of this study was to characterize the molecular mechanism of the antifibrotic role of HDAC1 inhibition. Specifically, treatment with MS-275, an HDAC1-3 inhibitor previously known to promote MMT reversal, induced the expression of several TGFBRI mRNA-targeting miRNAs. Among them, miR-769-5p ectopic expression was sufficient to promote MMT reversal and to limit MC migration and invasion, whereas miR-769-5p silencing further enhanced mesenchymal gene expression. These results were confirmed by HDAC1 genetic silencing. Interestingly, miR-769-5p silencing maintained mesenchymal features despite HDAC1 inhibition, thus indicating that it is necessary to drive MMT reversal induced by HDAC1 inhibition. Besides TGFBRI, miR-769-5p was demonstrated to target SMAD2/3 and PAI-1 expression directly. When analyzing molecular mechanisms underlying miR-769-5p expression, we found that the transcription factor Wilms’ tumor 1 (WT1), a master gene controlling MC development, binds to the miR-769-5p promoter favoring its expression. Interestingly, both WT1 expression and binding to miR-769-5p promoter were increased by HDAC1 inhibition and attenuated by TGFβ1 treatment. Finally, we explored the significance of these observations in the cell-to-cell communication: we evaluated the ability of miR-769-5p to be loaded into extracellular vesicles (EVs) and to promote MMT reversal in recipient mesenchymal-like MCs. Treatment of fibrotic MCs with EVs isolated from miR-769-5p over-expressing MCs promoted the down-regulation of specific mesenchymal targets and the reacquisition of an epithelial-like morphology. In conclusion, we highlighted an HDAC1-WT1-miR-769-5p axis potentially relevant for therapies aimed at counteracting organ fibrosis.

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Section: Discussionmentioning

confidence: 99%

“…Figure2) [20][21][22]. Moreover, data from the literature reported that miR-769-5p is loaded into osteosarcoma-derived EVs [23]. In this frame, we wondered whether the here demonstrated reprogramming activity of miR-769-5p could be horizontally transferred via EVs.…”

Section: Wt1-mediated Induction Of Mir769-5p Is Repressed In Fibrotic...mentioning

confidence: 94%

Restoration of WT1/miR-769-5p axis by HDAC1 inhibition promotes MMT reversal in mesenchymal-like mesothelial cells

et al. 2022

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“…The difference analysis of miR‐769‐5p was conducted through the TCGA database. Literatures reported that miR‐769‐5p has a role in the tumour as an oncogenic miRNA in hepatocellular carcinoma, osteosarcoma, glioma and so on 16–19 . However, the role of miR‐769‐5p in cisplatin resistance in GC has not been reported.…”

Section: Introductionmentioning

confidence: 99%

“…Literatures reported that miR-769-5p has a role in the tumour as an oncogenic miRNA in hepatocellular carcinoma, osteosarcoma, glioma and so on. [16][17][18][19] However, the role of miR-769-5p in cisplatin resistance in GC has not been reported. Therefore, the purpose of this study was to explore the relationship and mechanism between miR-769-5p and cisplatin resistance in GC.…”

Section: Introductionmentioning

confidence: 99%

Exosome‐transmitted miR‐769‐5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53

Jing

Xie

Ding

et al. 2022

Clinical & Translational Med

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Background Cisplatin resistance is the main cause of poor clinical prognosis in patients with gastric cancer (GC). Yet, the exact mechanism underlying cisplatin resistance remains unclear. Recent studies have suggested that exocrine miRNAs found in the tumor microenvironment participate in tumor metastasis and drug resistance. Methods Exosomes isolated from BGC823 and BGC823/DDP culture medium were characterized by transmission electron microscopy and differential ultracentrifugation, and miRNA expression profiles of BGC823 and BGC823/DDP cells derived exosomes were analyzed using miRNA microarray. In vivo and in vitro assays were used to identify roles of exosomal miR‐769‐5p and clarify the mechanism of exosomal miR‐769‐5p regulated the crosstalk between sensitive and resistant GC cells. Results In this study, we found that cisplatin‐resistant GC cells communicated with the tumor microenvironment by secreting microvesicles. MiR‐769‐5p was upregulated in GC tissues and enriched in the serum exosomes of cisplatin‐resistant patients. The biologically active miR‐769‐5p could be integrated into exosomes and delivered to sensitive cells, spreading cisplatin resistance. Underlying cellular and molecular mechanism was miR‐769‐5p targeting CASP9, thus inhibiting the downstream caspase pathway and promoting the degradation of the apoptosis‐related protein p53 through the ubiquitin‐proteasome pathway. Targeting miR‐769‐5p with its antagonist to treat cisplatin‐resistant GC cells can restore the cisplatin response, confirming that exosomal miR‐769‐5p can act as a key regulator of cisplatin resistance in GC. Conclusions These findings indicate that exosome‐transmitted miR‐769‐5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53. These findings reveal exosomal miR‐769‐5p derived from drug‐resistant cells can be used as a potential therapeutic predictor of anti‐tumor chemotherapy to enhance the effect of anti‐cancer chemotherapy, which provides a new treatment option for GC.

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“…There are similar phenomena in osteosarcoma. Most studies have shown that BMSCs promote the progression of osteosarcoma, and its mechanism includes the role of transferring exosome [ 38 ]. Interestingly, Zhou et al found that BMSCs can transfer miR-1913 into osteosarcoma cells through exosomes, reduce the expression level of NRSN2, and play a role in inhibiting the proliferation, migration and invasion of osteosarcoma [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

LncRNA XIST from the bone marrow mesenchymal stem cell derived exosome promotes osteosarcoma growth and metastasis through miR-655/ACLY signal

et al. 2022

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Background Long non-coding RNA X-inactive specific transcript (XIST) regulates the progression of a variety of tumors, including osteosarcoma. Bone marrow mesenchymal stem cells (BMSCs) can be recruited into osteosarcoma tissue and affect the progression by secreting exosomes. However, whether BMSCs derived exosomes transmit XIST to regulate the growth and metastasis of osteosarcoma and the related mechanism are still unclear. Method In this study, BMSCs derived exosomes were used to treat human osteosarcoma cells MG63 and 143B, and the level of XIST in BMSCs was intervened by siRNA. CCK-8, EdU, transwell assays were used to analyze the changes of cell proliferation, migration and invasion. Bioinformatics analysis, RNA pulldown and dual-luciferase reporter gene assays validated the targeted relationship of XIST with miR-655 and the interaction between miR-655 and ACLY 3’-UTR. 143B/LUC cell line was used to establish an animal model of in situ osteosarcoma to verify the found effects of XIST on osteosarcoma. Oil Red O staining, Western blot and so on were used to detect the changes of lipid deposition and protein expression. Results It was found that BMSCs derived exosomes promoted the proliferation, migration and invasion of osteosarcoma cells, and the down-regulation of XIST inhibited this effect. miR-655 mediated the role of BMSCs derived exosomal XIST in promoting the progression of osteosarcoma and down-regulation of miR-655 could reverse the effects of inhibiting XIST on the proliferation, migration and invasion of osteosarcoma cells. Meanwhile, animal level results confirmed that BMSCs derived exosomal XIST could promote osteosarcoma growth and lung metastasis by combining with miR-655. In-depth mechanism study showed that BMSCs derived exosomal XIST combined with miR-655 to increase the protein level of ACLY, which led to lipid deposition and activate β-catenin signal to promote the proliferation, migration and invasion of osteosarcoma cells. Conclusion This study showed that BMSCs derived exosomal XIST could enter osteosarcoma cells, bind and down-regulates the level of miR-655, resulting in an increase in the level of ACLY, thus increasing the lipid deposition and the activity of β-catenin signal to promote the growth and metastasis of osteosarcoma.

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Exosomal transfer of miR-769-5p promotes osteosarcoma proliferation and metastasis by targeting DUSP16

Cited by 21 publications

References 56 publications

Restoration of WT1/miR-769-5p axis by HDAC1 inhibition promotes MMT reversal in mesenchymal-like mesothelial cells

Restoration of WT1/miR-769-5p axis by HDAC1 inhibition promotes MMT reversal in mesenchymal-like mesothelial cells

Exosome‐transmitted miR‐769‐5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53

LncRNA XIST from the bone marrow mesenchymal stem cell derived exosome promotes osteosarcoma growth and metastasis through miR-655/ACLY signal

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