TRIM28(Tripartite motif-containing protein 28), a member of TRIM family, is aberrantly expressed and reportedly has different functions in many types of human cancer. However, the biological roles of TRIM28 and relate...TRIM28(Tripartite motif-containing protein 28), a member of TRIM family, is aberrantly expressed and reportedly has different functions in many types of human cancer. However, the biological roles of TRIM28 and related mechanism in colorectal cancer(CRC) remain unclear. Here, we showed that TRIM28 was downregulated in colorectal cancer compared with normal mucosa, especially at advanced stages, and acted as an independent prognostic factor of favorable outcome. Functional studies demonstrated that TRIM28 restrained CRC migration and invasion in vitro and in vivo. Mechanistically, we reported that CARM1(co-activator-associated arginine methyltransferase1) was a critical player downstream of TRIM28. TRIM28 interacted with CARM1, and protected CARM1 from proteasome-mediated degradation through physical protein-protein interaction to suppress CRC metastasis. Further, TRIM28 suppressed the migration and invasion of CRC cells through inhibiting WNT/b-catenin signaling in a CARM1-dependent manner, but independent of CARM10 s methyltransferase activity. The protein expression of CARM1 was positively correlated with TRIM28 in CRC tissues. Patients with high levels of TRIM28 and CARM1 had improved prognosis, whereas patients with low TRIM28 and CARM1 expression had the poor outcomes. Thus, our study reveals an inhibitory role of TRIM28 in CRC metastasis, which was achieved through a TRIM28-CARM1-WNT/b-catenin axis. This work provides potential prognostic and therapeutic targets for CRC treatment.展开更多
Background:MicroRNAs(miRNAs)play critical roles in corneal development and functional homeostasis.Our previous study identified miR-184 as one of the most highly expressed miRNAs in the corneal epithelium.Even though ...Background:MicroRNAs(miRNAs)play critical roles in corneal development and functional homeostasis.Our previous study identified miR-184 as one of the most highly expressed miRNAs in the corneal epithelium.Even though its expression level plummeted dramatically during corneal epithelial wound healing(CEWH),its precise role in mediating corneal epithelial renewal was unresolved.The present study aimed to reveal the function and mechanism of miR-184 in regulating CEWH.Methods:Quantitative RT-PCR analysis characterized the miR-184 expression pattern during CEWH in mice.Ectopic miR-184 injection determined its effect on this process in vivo.We evaluated the effects of miR-184 and its target genes on the proliferation,cell cycle,and migration of human corneal epithelial cells(HCECs)using MTS,flow cytometry,and wound-healing assay,respectively.Bioinformatic analysis,in conjunction with gene microarray analysis and cell-based luciferase assays,pinpointed gene targets of miR-184 contributing to CEWH.Results:MiR-184 underwent marked downregulation during mouse CEWH.Ectopic miR-184 overexpression delayed this process in mice.Furthermore,miR-184 transfection into HCECs significantly inhibited cell proliferation,cell cycle progression,and cell migration.MiR-184 directly targeted CDC25A,CARM1,and LASP1,and downregulated their expression in HCECs.CARM1 downregulation inhibited both HCEC proliferation and migration,whereas a decrease in LASP1 gene expression only inhibited migration.Conclusions:Our results demonstrate that miR-184 inhibits corneal epithelial cell proliferation and migration via targeting CDC25A,CARM1,and LASP1,suggesting it acts as a negative modulator during CEWH.Therefore,identifying strategies to suppress miR-184 expression levels has the potential to promote CEWH.展开更多
Background:MicroRNAs(miRNAs)play critical roles in corneal development and functional homeostasis.Our previous study identified miR-184 as one of the most highly expressed miRNAs in the corneal epithelium.Even though ...Background:MicroRNAs(miRNAs)play critical roles in corneal development and functional homeostasis.Our previous study identified miR-184 as one of the most highly expressed miRNAs in the corneal epithelium.Even though its expression level plummeted dramatically during corneal epithelial wound healing(CEWH),its precise role in mediating corneal epithelial renewal was unresolved.The present study aimed to reveal the function and mechanism of miR-184 in regulating CEWH.Methods:Quantitative reverse transcriptase polymerase chain reaction(RT-PCR)analysis characterized the miR-184 expression pattern during CEWH in mice.Ectopic miR-184 injection determined its effect on this process in vivo.We evaluated the effects of miR-184 and its target genes on the proliferation,cell cycle,and migration of human corneal epithelial cells(HCECs)using MTS,flow cytometry,and wound healing assay,respectively.Bioinformatic analysis,in conjunction with gene microarray analysis and cell-based luciferase assays,pinpointed gene targets of miR-184 contributing to CEWH.Results:MiR-184 underwent marked downregulation during mouse CEWH.Ectopic miR-184 overexpression delayed this process in mice.Furthermore,miR-184 transfection into HCECs significantly inhibited cell proliferation,cell cycle progression,and cell migration.MiR-184 directly targeted CDC25A,CARMI,and LASP1,and downregulated their expression in HCECs.CARM1 downregulation inhibited both HCEC proliferation and migration,whereas a decrease in LASPI gene expression only inhibited migration.Conclusi ons:Our results dem on strate that miR-184 inhibits corneal epithelial cell proliferation and migration via targeting CDC25A,CARMI,and LASPI,suggesting it acts as a negative modulator during CEWH.Therefore,identifying strategies to suppress miR-184 expression levels has the potential to promote CEWH.展开更多
Coactivator-associated arginine methyltransferase 1(CARM1)promotes the development and metastasis of estro-gen receptor alpha(ERa)-positive breast cancer.The function of CARM1 in triple-negative breast cancer(TNBC)is ...Coactivator-associated arginine methyltransferase 1(CARM1)promotes the development and metastasis of estro-gen receptor alpha(ERa)-positive breast cancer.The function of CARM1 in triple-negative breast cancer(TNBC)is still unclear and requires further exploration.Here,we report that CARM1 promotes proliferation,epithelial-mesen-chymal transition,and stemness in TNBC.CARM1 is upregulated in multiple cancers and its expression correlates with breast cancer progression.Genome-wide analysis of CARM1 showed that CARM1 is recruited by hypoxia-inducible factor-1 subunit alpha(HIF1A)and occupy the promoters of CDK4,Cyclin D1,β-Catenin,HIF1A,MALAT1,and SIX1 critically involved in cell cycle,HIF-1 signaling pathway,Wnt signaling pathway,VEGF signaling pathway,thereby modulating the proliferation and invasion of TNBC cells.We demonstrated that CARM1 is physically asso-ciated with and directly interacts with HIF1A.Moreover,we found that ellagic acid,an inhibitor of CARM1,can sup-press the proliferation and invasion of TNBC by directly inhibiting CDK4 expression.Our research has determined the molecular basis of CARM1 carcinogenesis in TNBC and its effective natural inhibitor,which may provide new ideas and drugs for cancer therapy.展开更多
Protein arginine methylation is a common post-translational modification involved in the regulation of various cellular functions. Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine meth...Protein arginine methylation is a common post-translational modification involved in the regulation of various cellular functions. Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that asymmetrically dimethylates histone H3 and non-histone proteins to regulate gene transcription. CARM1 has been found to play important roles in cell differentiation and development, cell cycle progression, autophagy, metabolism, pre-mRNA splicing and transportation, and DNA replication. In this review, we describe the molecular characteristics of CARM1 and summarize its roles in the regulation of cell differentiation and development in mammals.展开更多
基金supported by the Major State Basic Research Development Program of China (2015CB554007)the National Natural Science Foundation of China (81572866, 81773263 81773104, 31701202)+5 种基金the International Science and Technology Corporation Program of Chinese Ministry of Science and Technology (2014DFA32920)the Science and Technology Program of Chinese Ministry of Education (113044A)the Frontier Exploration Program of Huazhong University of Science and Technology (2015TS153)the Natural Science Foundation Program of Hubei Province (2015CFA049)the Research Fund of Public Welfare in Health Industry (201402015)the Research Fund of Public Welfare in Health Industry (201402015) from the Health and Family Plan Committee of China
文摘TRIM28(Tripartite motif-containing protein 28), a member of TRIM family, is aberrantly expressed and reportedly has different functions in many types of human cancer. However, the biological roles of TRIM28 and related mechanism in colorectal cancer(CRC) remain unclear. Here, we showed that TRIM28 was downregulated in colorectal cancer compared with normal mucosa, especially at advanced stages, and acted as an independent prognostic factor of favorable outcome. Functional studies demonstrated that TRIM28 restrained CRC migration and invasion in vitro and in vivo. Mechanistically, we reported that CARM1(co-activator-associated arginine methyltransferase1) was a critical player downstream of TRIM28. TRIM28 interacted with CARM1, and protected CARM1 from proteasome-mediated degradation through physical protein-protein interaction to suppress CRC metastasis. Further, TRIM28 suppressed the migration and invasion of CRC cells through inhibiting WNT/b-catenin signaling in a CARM1-dependent manner, but independent of CARM10 s methyltransferase activity. The protein expression of CARM1 was positively correlated with TRIM28 in CRC tissues. Patients with high levels of TRIM28 and CARM1 had improved prognosis, whereas patients with low TRIM28 and CARM1 expression had the poor outcomes. Thus, our study reveals an inhibitory role of TRIM28 in CRC metastasis, which was achieved through a TRIM28-CARM1-WNT/b-catenin axis. This work provides potential prognostic and therapeutic targets for CRC treatment.
基金This work was supported,in part,by the 973 Project(2012CB722303)from the Ministry of Science and Technology of China,Science Foundation of Wenzhou Medical University(QTJ11020)the Science and Technology Project of Wenzhou(Grant No.Y20160188).
文摘Background:MicroRNAs(miRNAs)play critical roles in corneal development and functional homeostasis.Our previous study identified miR-184 as one of the most highly expressed miRNAs in the corneal epithelium.Even though its expression level plummeted dramatically during corneal epithelial wound healing(CEWH),its precise role in mediating corneal epithelial renewal was unresolved.The present study aimed to reveal the function and mechanism of miR-184 in regulating CEWH.Methods:Quantitative RT-PCR analysis characterized the miR-184 expression pattern during CEWH in mice.Ectopic miR-184 injection determined its effect on this process in vivo.We evaluated the effects of miR-184 and its target genes on the proliferation,cell cycle,and migration of human corneal epithelial cells(HCECs)using MTS,flow cytometry,and wound-healing assay,respectively.Bioinformatic analysis,in conjunction with gene microarray analysis and cell-based luciferase assays,pinpointed gene targets of miR-184 contributing to CEWH.Results:MiR-184 underwent marked downregulation during mouse CEWH.Ectopic miR-184 overexpression delayed this process in mice.Furthermore,miR-184 transfection into HCECs significantly inhibited cell proliferation,cell cycle progression,and cell migration.MiR-184 directly targeted CDC25A,CARM1,and LASP1,and downregulated their expression in HCECs.CARM1 downregulation inhibited both HCEC proliferation and migration,whereas a decrease in LASP1 gene expression only inhibited migration.Conclusions:Our results demonstrate that miR-184 inhibits corneal epithelial cell proliferation and migration via targeting CDC25A,CARM1,and LASP1,suggesting it acts as a negative modulator during CEWH.Therefore,identifying strategies to suppress miR-184 expression levels has the potential to promote CEWH.
基金supported,in part,by the 973 Project(Grant No.2012CB722303)the Ministry of Science and Technology of China,Science Foundation of Wenzhou Medical University(Grant No.QTJ11020)the Science and Technology Project of Wenzhou(Grant No.Y20160188).
文摘Background:MicroRNAs(miRNAs)play critical roles in corneal development and functional homeostasis.Our previous study identified miR-184 as one of the most highly expressed miRNAs in the corneal epithelium.Even though its expression level plummeted dramatically during corneal epithelial wound healing(CEWH),its precise role in mediating corneal epithelial renewal was unresolved.The present study aimed to reveal the function and mechanism of miR-184 in regulating CEWH.Methods:Quantitative reverse transcriptase polymerase chain reaction(RT-PCR)analysis characterized the miR-184 expression pattern during CEWH in mice.Ectopic miR-184 injection determined its effect on this process in vivo.We evaluated the effects of miR-184 and its target genes on the proliferation,cell cycle,and migration of human corneal epithelial cells(HCECs)using MTS,flow cytometry,and wound healing assay,respectively.Bioinformatic analysis,in conjunction with gene microarray analysis and cell-based luciferase assays,pinpointed gene targets of miR-184 contributing to CEWH.Results:MiR-184 underwent marked downregulation during mouse CEWH.Ectopic miR-184 overexpression delayed this process in mice.Furthermore,miR-184 transfection into HCECs significantly inhibited cell proliferation,cell cycle progression,and cell migration.MiR-184 directly targeted CDC25A,CARMI,and LASP1,and downregulated their expression in HCECs.CARM1 downregulation inhibited both HCEC proliferation and migration,whereas a decrease in LASPI gene expression only inhibited migration.Conclusi ons:Our results dem on strate that miR-184 inhibits corneal epithelial cell proliferation and migration via targeting CDC25A,CARMI,and LASPI,suggesting it acts as a negative modulator during CEWH.Therefore,identifying strategies to suppress miR-184 expression levels has the potential to promote CEWH.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.41931291,42125707,81802816,81902882,and 82273403)Major State Basic Research Development Program of China(2022YFA1103402)+1 种基金Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT310027,2021-RC310-006)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-12M-1-018).
文摘Coactivator-associated arginine methyltransferase 1(CARM1)promotes the development and metastasis of estro-gen receptor alpha(ERa)-positive breast cancer.The function of CARM1 in triple-negative breast cancer(TNBC)is still unclear and requires further exploration.Here,we report that CARM1 promotes proliferation,epithelial-mesen-chymal transition,and stemness in TNBC.CARM1 is upregulated in multiple cancers and its expression correlates with breast cancer progression.Genome-wide analysis of CARM1 showed that CARM1 is recruited by hypoxia-inducible factor-1 subunit alpha(HIF1A)and occupy the promoters of CDK4,Cyclin D1,β-Catenin,HIF1A,MALAT1,and SIX1 critically involved in cell cycle,HIF-1 signaling pathway,Wnt signaling pathway,VEGF signaling pathway,thereby modulating the proliferation and invasion of TNBC cells.We demonstrated that CARM1 is physically asso-ciated with and directly interacts with HIF1A.Moreover,we found that ellagic acid,an inhibitor of CARM1,can sup-press the proliferation and invasion of TNBC by directly inhibiting CDK4 expression.Our research has determined the molecular basis of CARM1 carcinogenesis in TNBC and its effective natural inhibitor,which may provide new ideas and drugs for cancer therapy.
基金supported by Funding for Top-notch Personnel from Shandong First Medical University and Taishan Scholars Program(No.ts 2019097).
文摘Protein arginine methylation is a common post-translational modification involved in the regulation of various cellular functions. Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that asymmetrically dimethylates histone H3 and non-histone proteins to regulate gene transcription. CARM1 has been found to play important roles in cell differentiation and development, cell cycle progression, autophagy, metabolism, pre-mRNA splicing and transportation, and DNA replication. In this review, we describe the molecular characteristics of CARM1 and summarize its roles in the regulation of cell differentiation and development in mammals.
