miR-504 plays a pivotal role in the progression of oral cancer.However,the underlying mechanism remains elusive in vivo.Here,we find that miR-504 is significantly down-regulated in oral cancer patients.We generate miR...miR-504 plays a pivotal role in the progression of oral cancer.However,the underlying mechanism remains elusive in vivo.Here,we find that miR-504 is significantly down-regulated in oral cancer patients.We generate miR-504 knockout mice(miR-504^(-/-))using CRISPR/Cas9 technology to investigate its impact on the malignant progression of oral cancer under exposure to 4-Nitroquinoline N-oxide(4NQO).We show that the deletion of miR-504 does not affect phenotypic characteristics,body weight,reproductive performance,and survival in mice,but results in changes in the blood physiological and biochemical indexes of the mice.Moreover,with 4NQO treatment,miR-504^(-/-)mice exhibit more pronounced pathological changes char-acteristic of oral cancer.RNA sequencing shows that the differentially expressed genes observed in samples from miR-504^(-/-)mice with oral cancer are involved in regulating cell metabolism,cytokine acti-vation,and lipid metabolism-related pathways.Additionally,these differentially expressed genes are significantly enriched in lipid metabolism pathways that influence immune cell infiltration within the tumor microenvironment,thereby accelerating tumor development progression.Collectively,our results suggest that knockout of miR-504 accelerates malignant progression in 4NQO-induced oral cancer by regulating tumor cell proliferation and lipid metabolism,affecting immune cell infiltration.展开更多
Background:Intracellular accumulation of the microtubule-associated protein tau and its hyperphosphorylated forms is a key neuropathological feature of Alzheimer’s disease(AD).Melatonin has been shown to prevent tau ...Background:Intracellular accumulation of the microtubule-associated protein tau and its hyperphosphorylated forms is a key neuropathological feature of Alzheimer’s disease(AD).Melatonin has been shown to prevent tau hyperphosphorylation in cellular and animal models.However,the molecular mechanisms by which melatonin attenuates tau hyperphosphorylation and tau-related pathologies are not fully understood.Methods:Immunofluorescence,immunoblotting analysis and thioflavin-S staining were employed to examine the effects of early and late treatment of melatonin on tau-related pathology in hTau mice,in which nonmutated human tau is overexpressed on a mouse tau knockout background.High-throughput microRNA(miRNA)sequencing,quantitative RT-PCR,luciferase reporter assay and immunoblotting analysis were performed to determine the molecular mechanism.Results:We found that both early and late treatment of melatonin efficiently decreased the phosphorylation of soluble and insoluble tau at sites related to AD.Moreover,melatonin significantly reduced the number of neurofibrillary tangles(NFTs)and attenuated neuronal loss in the cortex and hippocampus.Furthermore,using miRNA microarray analysis,we found that miR-504-3p expression was upregulated by melatonin in the hTau mice.The administration of miR-504-3p mimics dramatically decreased tau phosphorylation by targeting p39,an activator of the well-known tau kinase cyclin-dependent kinase 5(CDK5).Compared with miR-504-3p mimics alone,co-treatment with miR-504-3p mimics and p39 failed to reduce tau hyperphosphorylation.Conclusions:Our results suggest for the first time that melatonin alleviates tau-related pathologies through upregulation of miR-504-3p expression by targeting the p39/CDK5 axis and provide novel insights into AD treatment strategies.展开更多
基金This work was supported by the National Natural Science Foundation of China(31970513 to G.S.)the Central Government's Guide to Local Science and Technology Development Fund(YDZJSX2022A060 to G.S.)+2 种基金the special funds for Science and Technology Innovation Teams of Shanxi Province(202204051002032 to G.S.)the Shanxi Province Higher Education"BillionProject"Science and Technology Guidance Project(BYJLO16 to G.S.)the Natural Science Foundation of Shanxi Province(20210302124093 to J.G.).
文摘miR-504 plays a pivotal role in the progression of oral cancer.However,the underlying mechanism remains elusive in vivo.Here,we find that miR-504 is significantly down-regulated in oral cancer patients.We generate miR-504 knockout mice(miR-504^(-/-))using CRISPR/Cas9 technology to investigate its impact on the malignant progression of oral cancer under exposure to 4-Nitroquinoline N-oxide(4NQO).We show that the deletion of miR-504 does not affect phenotypic characteristics,body weight,reproductive performance,and survival in mice,but results in changes in the blood physiological and biochemical indexes of the mice.Moreover,with 4NQO treatment,miR-504^(-/-)mice exhibit more pronounced pathological changes char-acteristic of oral cancer.RNA sequencing shows that the differentially expressed genes observed in samples from miR-504^(-/-)mice with oral cancer are involved in regulating cell metabolism,cytokine acti-vation,and lipid metabolism-related pathways.Additionally,these differentially expressed genes are significantly enriched in lipid metabolism pathways that influence immune cell infiltration within the tumor microenvironment,thereby accelerating tumor development progression.Collectively,our results suggest that knockout of miR-504 accelerates malignant progression in 4NQO-induced oral cancer by regulating tumor cell proliferation and lipid metabolism,affecting immune cell infiltration.
基金the National Natural Science Foundation of China(81901071 and 81970993)the Natural Science Foundation of Fujian Province(2019J01297 and 2019J05072)the Medical Innovation Grant of Fujian Province(2019-CX-36).
文摘Background:Intracellular accumulation of the microtubule-associated protein tau and its hyperphosphorylated forms is a key neuropathological feature of Alzheimer’s disease(AD).Melatonin has been shown to prevent tau hyperphosphorylation in cellular and animal models.However,the molecular mechanisms by which melatonin attenuates tau hyperphosphorylation and tau-related pathologies are not fully understood.Methods:Immunofluorescence,immunoblotting analysis and thioflavin-S staining were employed to examine the effects of early and late treatment of melatonin on tau-related pathology in hTau mice,in which nonmutated human tau is overexpressed on a mouse tau knockout background.High-throughput microRNA(miRNA)sequencing,quantitative RT-PCR,luciferase reporter assay and immunoblotting analysis were performed to determine the molecular mechanism.Results:We found that both early and late treatment of melatonin efficiently decreased the phosphorylation of soluble and insoluble tau at sites related to AD.Moreover,melatonin significantly reduced the number of neurofibrillary tangles(NFTs)and attenuated neuronal loss in the cortex and hippocampus.Furthermore,using miRNA microarray analysis,we found that miR-504-3p expression was upregulated by melatonin in the hTau mice.The administration of miR-504-3p mimics dramatically decreased tau phosphorylation by targeting p39,an activator of the well-known tau kinase cyclin-dependent kinase 5(CDK5).Compared with miR-504-3p mimics alone,co-treatment with miR-504-3p mimics and p39 failed to reduce tau hyperphosphorylation.Conclusions:Our results suggest for the first time that melatonin alleviates tau-related pathologies through upregulation of miR-504-3p expression by targeting the p39/CDK5 axis and provide novel insights into AD treatment strategies.
