miR-151a-3p-rich small extracellular vesicles derived from gastric cancer accelerate liver metastasis via initiating a hepatic stemness-enhancing niche

Li, Bowen; Xia, Yiwen; Lv, Jialun; Wang, Weizhi; Xuan, Zhe; Chen, Cen; Jiang, Tianlu; Fang, Lang; Wang, Linjun; Li, Zheng; He, Zhongyuan; Li, Qingya; Xie, Li; Qiu, Shengkui; Zhang, Lu; Zhang, Diancai; Xu, Hao; Xu, Zekuan

doi:10.1038/s41388-021-02011-0

Cited by 34 publications

(27 citation statements)

References 62 publications

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“…Meanwhile, we found that the m6A regulatory factor also had a strong correlation with endoplasmic reticulum oxidative stress and mitochondrial autophagy pathway, which is consistent with our previous study. Small extracellular vesicles-miR-151a-3p targeted YTHDF3 to reduce the transcriptional inhibitory activity of SP3 , promote the transactivation of TGF-β1 in KCs, and then activate the SMAD2/3 pathway to enhance the stem cell-like characteristics of the incoming GC cells ( Li et al, 2021 ). TGF-β 1 plays a vital role in maintaining the homeostasis of articular cartilage and subchondral bone ( He et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

m6A Regulator-Mediated RNA Methylation Modification Patterns Regulate the Immune Microenvironment in Osteoarthritis

Duan

Yan

et al. 2022

Front. Genet.

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Epigenetic regulation, particularly RNA n6 methyl adenosine (m6A) modification, plays an important role in the immune response. However, the regulatory role of m6A in the immune microenvironment in osteoarthritis (OA) remains unclear. Accordingly, we systematically studied RNA modification patterns mediated by 23 m6A regulators in 38 samples and discussed the characteristics of the immune microenvironment modified by m6A. Next, we constructed a novel OA m6A nomogram, an m6A-transcription factor-miRNA network, and a drug network. Healthy and OA samples showed distinct m6A regulatory factor expression patterns. YTHDF3 expression was upregulated in OA samples and positively correlated with type II helper cells and TGFb family member receptors. Furthermore, three different RNA modification patterns were mediated by 23 m6A regulatory factors; in Mode 3, the expression levels of YTHDF3, type II T helper cells, and TGFb family member receptors were upregulated. Pathways related to endoplasmic reticulum oxidative stress and mitochondrial autophagy showed a strong correlation with the regulatory factors associated with Mode 3 and 23 m6A regulatory factors. Through RT-qPCR we validated that SREBF2 and EGR1 as transcription factors of YTHDF3 and IGF2BP3 are closely associated with the development of OA, hsa-miR-340 as a miRNA for YTHDF3 and IGF2BP3 was involved in the development of OA, we also detected the protein expression levels of IGF2BP3, YTHDF3, EGR1 and SREBF2 by western blotting, and the results were consistent with PCR. Overall, the constructed nomogram can facilitate the prediction of OA risk.

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Section: Discussionmentioning

confidence: 99%

m6A Regulator-Mediated RNA Methylation Modification Patterns Regulate the Immune Microenvironment in Osteoarthritis

Duan

Yan

et al. 2022

Front. Genet.

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“…Gastric cancer cells with high liver metastatic potential (MKN45-HL) were successfully established in our previous study [ 21 ]. In brief, 2 million MKN45 cells stably transfected with a double-labeled empty GFP-Flag lentivirus (Shanghai Gene Pharma) were injected into the hepatic portal vein of 6-week-old female BALB/c nude mice.…”

Section: Methodsmentioning

confidence: 99%

“…Exosome tracking assays were performed as previously described [ 21 ]. A total of 10 μg exosomes were first mixed with Diluent C buffer containing 4 μl PKH26/67 dye (Sigma, USA) for 5 min and then incubated with 1% BSA solution at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Gastric cancer-derived exosomal miR-519a-3p promotes liver metastasis by inducing intrahepatic M2-like macrophage-mediated angiogenesis

Qiu

Xie

Chen

et al. 2022

J Exp Clin Cancer Res

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Background Liver metastasis (LM) is a major obstacle to the prognosis of gastric cancer (GC) patients, but the molecular mechanism underlying gastric cancer liver metastasis (GC-LM) remains unknown. Exosomes have been identified as an important mediator of communication between tumor cells and the microenvironment. Therefore, we sought to investigate the effects of primary GC cells on the liver microenvironment and the role of exosomal microRNAs (exo-miRNA) in GC-LM. Methods Sequential differential centrifugation, transmission electron microscopy and NanoSight analysis were used to extract and characterize exosomes. MicroRNA sequencing in GC-derived exosomes and mRNA sequencing in PMA-treated THP-1 cells were used to identify differentially expressed miRNAs in exosomes and the functional targets of exosomal miR-519a-3p (exo-miR-519a-3p) in macrophages, respectively. Tracing and internalization of exosomes and transfer of exo-miR-519a-3p were observed by immunofluorescence. Tubule formation assays, aortic ring assays, and exosome-educated GC-LM model were used to investigate the roles of GC-derived exosomes and exo-miR-519a-3p in angiogenesis and GC-LM. Luciferase reporter assay, qRT-PCR, Western blot, ELISA, flow cytometry and immunofluorescence were used to investigate the regulatory mechanism of exo-miR-519a-3p at GC-LM. Results The expression level of miR-519a-3p in serum exosomes was significantly higher in GC-LM patients than in patients without LM, and high expression of exo-miR-519a-3p indicates a worse prognosis. GC-derived exosomes are mainly accumulated in the liver and internalized by intrahepatic macrophages. Mechanistically, exo-miR-519a-3p activates the MAPK/ERK pathway by targeting DUSP2, thereby causing M2-like polarization of macrophages. M2-like polarized macrophages accelerate GC-LM by inducing angiogenesis and promoting intrahepatic premetastatic niche formation. Conclusions Our results indicate that exo-miR-519a-3p plays a critical role in mediating crosstalk between primary GC cells and intrahepatic macrophages and is a potential therapeutic target for GC-LM.

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“…On the other hand, in non-small cell lung cancer (NSCLC), it acts as an oncomiR by enhancing proliferation, migration, and partial epithelial-to-mesenchymal transition of NSCLC cells by targeting E-cadherin 28 . Extracellular vesicles containing mir-151a-3p facilitate liver metastasis and could be a promising biomarker for diagnosis in gastric cancer 29 . In our study, we detected the upregulation of mir-151a-3p in MM patient samples by bioinformatics analysis.…”

Section: Discussionmentioning

confidence: 99%

In silico and in vitro analysis of differentially expressed microRNAs, circular RNAs, and p53 in bortezomib-resistant multiple myeloma

2022

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Background: Multiple myeloma (MM), which constitutes 1% of all cancers, remains incurable due to the acquisition of drug resistance. Proteasome inhibitor therapy such as bortezomib (BTZ), one of the key therapies used to treat MM, is impeded by the occurrence of BTZ resistance. The precise mechanism underlying this acquired BTZ resistance in MM is not yet well understood. In recent times, the role of non-coding RNAs, such as microRNAs (miRNAs) and circular RNAs (circRNAs), in cancer progression and drug resistance has been demonstrated. The present study aimed to identify differentially expressed miRNAs (DEmiRs), circRNAs, and target genes in BTZ-resistant MM in silico and in vitro. Methods: DEmiRs were obtained and analyzed from microarray datasets of MM patients from the Gene Expression Omnibus (GEO) database using GEO2R. Targets of a DEmiR were detected using mirDIP software. Gene ontology and pathway enrichment analysis of the targets were executed using the DAVID database. A protein-protein interaction network of targets was constructed and analyzed using the STRING database and Cytoscape tool. Expression levels of a DEmiR and an interacting circRNA were assessed by qRT-PCR. Target gene expression was assessed by qRT-PCR and western blot. Results: Among the identified DEmiRs, hsa-mir-151a-3p was found to be upregulated in BTZ-resistant MM. One circRNA, hsa_circ_0000073, that was predicted to interact with hsa-mir-151a-3p using the CircInteractome platform, was downregulated in BTZ-resistant MM. Among the targets of hsa-mir-151a-3p, p53 was downregulated at both the transcript and protein levels in BTZ-resistant MM. Conclusions: This study indicates that these molecular players could be implicated in BTZ-resistant MM.

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miR-151a-3p-rich small extracellular vesicles derived from gastric cancer accelerate liver metastasis via initiating a hepatic stemness-enhancing niche

Cited by 34 publications

References 62 publications

m6A Regulator-Mediated RNA Methylation Modification Patterns Regulate the Immune Microenvironment in Osteoarthritis

m6A Regulator-Mediated RNA Methylation Modification Patterns Regulate the Immune Microenvironment in Osteoarthritis

Gastric cancer-derived exosomal miR-519a-3p promotes liver metastasis by inducing intrahepatic M2-like macrophage-mediated angiogenesis

In silico and in vitro analysis of differentially expressed microRNAs, circular RNAs, and p53 in bortezomib-resistant multiple myeloma

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