Dorsal root ganglia neurons gradually lose their axonal regeneration ability during development and aging.To explore molecules that enhance axonal regeneration,we screened growth factors with differential gene express...Dorsal root ganglia neurons gradually lose their axonal regeneration ability during development and aging.To explore molecules that enhance axonal regeneration,we screened growth factors with differential gene expression patterns in the dorsal root ganglias of young adult and aged animals following sciatic nerve injury.In young adult animals,two transforming growth factor beta-related factors,activin A and angiopoietin 2,were found to be upregulated post nerve injury.Treatment of isolated dorsal root ganglia explants and cultured dorsal root ganglia neurons of neonatal and young adult rats with recombinant activin A or angiopoietin 2 protein stimulated neurite outgrowth and axonal elongation.The administration of recombinant activin A or angiopoietin 2 protein to sciatic nerve crush-injured dorsal root ganglias also supported the growth of sensory neurons and facilitated nerve regeneration in both young adult and aged rats.Using RNA sequencing,we characterized genetic changes in dorsal root ganglia neurons following recombinant activin A or angiopoietin 2 treatment,revealing the unique mechanisms of these transforming growth factor beta-related factors.Recombinant activin A elicited changes in the gene expression of cytoskeleton-related Gper1 and activated extracellular signal-regulated kinase signaling,while angiopoietin 2 increased the expression of the transcription factor gene E2f2.Our identification of activin A and angiopoietin 2 as crucial promotional factors of axonal regeneration may guide future therapeutic strategies for the treatment of nerve injury.展开更多
Breast cancer metastasis is the root cause of deaths from breast cancer.Currently,endocrine therapy resistance in estrogen receptor(ER)-positive(ER^(+))breast cancer remains a major clinical issue.Moreover,ER-negative...Breast cancer metastasis is the root cause of deaths from breast cancer.Currently,endocrine therapy resistance in estrogen receptor(ER)-positive(ER^(+))breast cancer remains a major clinical issue.Moreover,ER-negative(ER^(-))breast cancer is often associated with distant recurrence and death.G-protein-coupled ER(GPER1)participates in endocrine therapy resistance and is involved in the malignant progression of breast cancer.However,the underlying detailed mechanisms remain obscure.Here we investigated the role and mechanism of GPER1 in the activation of focal adhesion kinase(FAK)using ER^(+)or ERbreast cancer cell lines.In SK-Br-3 cells(ERa^(-)/β/GPER1^(+)),both 17b-estradiol(E2)and the GPER1 agonist G1 resulted in rapid FAK phosphorylation.This action is due to GPER1 interaction with the non-receptor tyrosine kinase c-Src and subsequent activation of nuclear factor kappa B(NF-kB)signaling.Silencing of GPER1,c-Src or the nuclear factor kappa B p65 subunit blocked E2-or G1-induced SK-Br-3 cell migration and invasion.In MCF-7 cells(ERa^(+)/β(+)/GPER1^(+)),silencing of GPER1,but not ERa or ERb,abolished FAK phosphorylation induced by E2 or G1.In MDA-MB-231 cells(ERa^(-)/β^(+)/GPER1^(-)),E2 or G1 was also unable to stimulate E2-induced FAK phosphorylation.However,E2 and G1 regained the ability to induce FAK phosphorylation under conditions of overexpression of GPER1.In conclusion,we demonstrated that GPER1,but not ERa or ERb,mediates FAK phosphorylation induced by E2 via the c-Src/p65 signaling pathway,which enhances cell migration and invasion.These findings may shed light on novel therapeutic strategies based on GPER1/FAK signaling pathways in suppression of breast cancer metastasis.展开更多
基金supported by Major Program of National Natural Science Foundation of China,No.92368207Frontier Leading Technology BasicResearch Major Project of Jiangsu Province,No.BK20232023(both to XG).
文摘Dorsal root ganglia neurons gradually lose their axonal regeneration ability during development and aging.To explore molecules that enhance axonal regeneration,we screened growth factors with differential gene expression patterns in the dorsal root ganglias of young adult and aged animals following sciatic nerve injury.In young adult animals,two transforming growth factor beta-related factors,activin A and angiopoietin 2,were found to be upregulated post nerve injury.Treatment of isolated dorsal root ganglia explants and cultured dorsal root ganglia neurons of neonatal and young adult rats with recombinant activin A or angiopoietin 2 protein stimulated neurite outgrowth and axonal elongation.The administration of recombinant activin A or angiopoietin 2 protein to sciatic nerve crush-injured dorsal root ganglias also supported the growth of sensory neurons and facilitated nerve regeneration in both young adult and aged rats.Using RNA sequencing,we characterized genetic changes in dorsal root ganglia neurons following recombinant activin A or angiopoietin 2 treatment,revealing the unique mechanisms of these transforming growth factor beta-related factors.Recombinant activin A elicited changes in the gene expression of cytoskeleton-related Gper1 and activated extracellular signal-regulated kinase signaling,while angiopoietin 2 increased the expression of the transcription factor gene E2f2.Our identification of activin A and angiopoietin 2 as crucial promotional factors of axonal regeneration may guide future therapeutic strategies for the treatment of nerve injury.
基金This work was supported by the National Natural Science Foundation of China(to XDF,no.81471426)by the Project of Department of Education of Guangdong Province(to XDF,no.2015KTSCX109)by the National Funds of Developing Local Colleges and Universities(to XDF,no.B16056001).
文摘Breast cancer metastasis is the root cause of deaths from breast cancer.Currently,endocrine therapy resistance in estrogen receptor(ER)-positive(ER^(+))breast cancer remains a major clinical issue.Moreover,ER-negative(ER^(-))breast cancer is often associated with distant recurrence and death.G-protein-coupled ER(GPER1)participates in endocrine therapy resistance and is involved in the malignant progression of breast cancer.However,the underlying detailed mechanisms remain obscure.Here we investigated the role and mechanism of GPER1 in the activation of focal adhesion kinase(FAK)using ER^(+)or ERbreast cancer cell lines.In SK-Br-3 cells(ERa^(-)/β/GPER1^(+)),both 17b-estradiol(E2)and the GPER1 agonist G1 resulted in rapid FAK phosphorylation.This action is due to GPER1 interaction with the non-receptor tyrosine kinase c-Src and subsequent activation of nuclear factor kappa B(NF-kB)signaling.Silencing of GPER1,c-Src or the nuclear factor kappa B p65 subunit blocked E2-or G1-induced SK-Br-3 cell migration and invasion.In MCF-7 cells(ERa^(+)/β(+)/GPER1^(+)),silencing of GPER1,but not ERa or ERb,abolished FAK phosphorylation induced by E2 or G1.In MDA-MB-231 cells(ERa^(-)/β^(+)/GPER1^(-)),E2 or G1 was also unable to stimulate E2-induced FAK phosphorylation.However,E2 and G1 regained the ability to induce FAK phosphorylation under conditions of overexpression of GPER1.In conclusion,we demonstrated that GPER1,but not ERa or ERb,mediates FAK phosphorylation induced by E2 via the c-Src/p65 signaling pathway,which enhances cell migration and invasion.These findings may shed light on novel therapeutic strategies based on GPER1/FAK signaling pathways in suppression of breast cancer metastasis.
