Due to its difficulty in early diagnosis and lack of sensitivity to chemotherapy and radiotherapy,renal cell carcinoma(RCC)remains to be a frequent cause of cancer-related death.Here,we probed into new targets for its ...Due to its difficulty in early diagnosis and lack of sensitivity to chemotherapy and radiotherapy,renal cell carcinoma(RCC)remains to be a frequent cause of cancer-related death.Here,we probed into new targets for its early diagnosis and treatment for RCC.microRNA(miRNA)data of M2-EVs and RCC were searched on the Gene Expression Omnibus database,followed by the prediction of the potential downstream target.Expression of target genes was measured via RT-qPCR and Western blot,respectively.M2 macrophage was obtained viaflow cytometry with M2-EVs extracted.The binding ability of miR-342-3p to NEDD4L and to CEP55 ubiquitination was studied with their roles in the physical abilities of RCC cells assayed.Subcutaneous tumor-bearing mouse models and lung metastasis models were prepared to observe in vivo role of target genes.M2-EVs induced RCC growth and metastasis.miR-342-3p showed high expression in both M2-EVs and RCC cells.M2-EVs carrying miR-342-3p promoted RCC cell abilities to proliferate,invade and migrate.In RCC cells,M2-EV-derived miR-342-3p could specifically bind to NEDD4L and consequently elevate CEP55 protein expression via suppressing NEDD4L,thereby exerting tumor-promoting effects.CEP55 could be degraded by ubiquitination under the function of NEDD4L,and miR-342-3p delivered by M2-EVs facilitated the RCC occurrence and development by activating the PI3K/AKT/mTOR signaling pathway.In conclusion,M2-EVs promote RCC growth and metastasis by delivering miR-342-3p to suppress NEDD4L and subsequently inhibit CEP55 ubiquitination and degradation via activation of the PI3K/AKT/mTOR signaling pathway,strongly driving the proliferative,migratory and invasive of RCC cells.展开更多
Multiple sclerosis(MS)is a chronic and incurable autoimmune neurodegenerative disease of the central nervous system.Although the symptoms of MS can be managed by vitamin D3 treatment alone,this condition cannot be com...Multiple sclerosis(MS)is a chronic and incurable autoimmune neurodegenerative disease of the central nervous system.Although the symptoms of MS can be managed by vitamin D3 treatment alone,this condition cannot be completely eradicated.Thus,there might be unknown factors capable of regulating the vitamin D receptor(VDR).Genome-wide analysis showed that miRNAs were associated with VDRs.We sought to determine the role and mechanism of action of miRNA-125a-5p and VDRs in a model of MS,mice with experimental autoimmune encephalomyelitis(EAE),which was induced by myelin oligodendrocyte glycoprotein 35–55 peptides.EAE mice showed decreased mean body weight but increased mean clinical scores compared with vehicle or control mice.And inflammatory infiltration was found in the lumbosacral spinal cord of EAE mice.In addition,VDR expression was significantly lower while the expression of miR-125a-5p was markedly higher in the spinal ventral horn of EAE mice than in vehicle or control mice.Importantly,activation of VDRs by paricalcitol or inhibition of miR-125a-5p by its antagomir markedly decreased the mean clinical scores in EAE mice.Interestingly,VDR and miR-125a-5p were co-localized in the same neurons of the ventral horn.More importantly,inhibition of miR-125a-5p remarkably blocked the decrease of VDRs in EAE mice.These results support a critical role for miR-125a-5p in modulating VDR activity in EAE and suggest potential novel therapeutic interventions.展开更多
基金supported by the Science and Technology Department of Sichuan Province(2015SZ0117,2019YJ0701,and 2021YJ0239).
文摘Due to its difficulty in early diagnosis and lack of sensitivity to chemotherapy and radiotherapy,renal cell carcinoma(RCC)remains to be a frequent cause of cancer-related death.Here,we probed into new targets for its early diagnosis and treatment for RCC.microRNA(miRNA)data of M2-EVs and RCC were searched on the Gene Expression Omnibus database,followed by the prediction of the potential downstream target.Expression of target genes was measured via RT-qPCR and Western blot,respectively.M2 macrophage was obtained viaflow cytometry with M2-EVs extracted.The binding ability of miR-342-3p to NEDD4L and to CEP55 ubiquitination was studied with their roles in the physical abilities of RCC cells assayed.Subcutaneous tumor-bearing mouse models and lung metastasis models were prepared to observe in vivo role of target genes.M2-EVs induced RCC growth and metastasis.miR-342-3p showed high expression in both M2-EVs and RCC cells.M2-EVs carrying miR-342-3p promoted RCC cell abilities to proliferate,invade and migrate.In RCC cells,M2-EV-derived miR-342-3p could specifically bind to NEDD4L and consequently elevate CEP55 protein expression via suppressing NEDD4L,thereby exerting tumor-promoting effects.CEP55 could be degraded by ubiquitination under the function of NEDD4L,and miR-342-3p delivered by M2-EVs facilitated the RCC occurrence and development by activating the PI3K/AKT/mTOR signaling pathway.In conclusion,M2-EVs promote RCC growth and metastasis by delivering miR-342-3p to suppress NEDD4L and subsequently inhibit CEP55 ubiquitination and degradation via activation of the PI3K/AKT/mTOR signaling pathway,strongly driving the proliferative,migratory and invasive of RCC cells.
基金supported by the International Science and Technology Cooperation Plan of Guizhou Province,China[(2013)7027]the National Natural Science Foundation of China(81471137 and 31730040).
文摘Multiple sclerosis(MS)is a chronic and incurable autoimmune neurodegenerative disease of the central nervous system.Although the symptoms of MS can be managed by vitamin D3 treatment alone,this condition cannot be completely eradicated.Thus,there might be unknown factors capable of regulating the vitamin D receptor(VDR).Genome-wide analysis showed that miRNAs were associated with VDRs.We sought to determine the role and mechanism of action of miRNA-125a-5p and VDRs in a model of MS,mice with experimental autoimmune encephalomyelitis(EAE),which was induced by myelin oligodendrocyte glycoprotein 35–55 peptides.EAE mice showed decreased mean body weight but increased mean clinical scores compared with vehicle or control mice.And inflammatory infiltration was found in the lumbosacral spinal cord of EAE mice.In addition,VDR expression was significantly lower while the expression of miR-125a-5p was markedly higher in the spinal ventral horn of EAE mice than in vehicle or control mice.Importantly,activation of VDRs by paricalcitol or inhibition of miR-125a-5p by its antagomir markedly decreased the mean clinical scores in EAE mice.Interestingly,VDR and miR-125a-5p were co-localized in the same neurons of the ventral horn.More importantly,inhibition of miR-125a-5p remarkably blocked the decrease of VDRs in EAE mice.These results support a critical role for miR-125a-5p in modulating VDR activity in EAE and suggest potential novel therapeutic interventions.
