The neurotrophic signaling of glial cell line-derived neurotrophic factor(GDNF)with its canonical receptor,the receptor tyrosine kinase RET,coupled together with the GDNF family receptor alpha 1 is important for dopam...The neurotrophic signaling of glial cell line-derived neurotrophic factor(GDNF)with its canonical receptor,the receptor tyrosine kinase RET,coupled together with the GDNF family receptor alpha 1 is important for dopaminergic neuron survival and physiology in cell culture experiments and animal models.This prompted the idea to try GDNF/RET signaling as a therapeutic approach to treat Parkinson’s disease with the hallmark of dopaminergic cell death in the substantia nigra of the midbrain.Despite several clinical trials with GDNF in Parkinson’s disease patients,which mainly focused on optimizing the GDNF delivery technique,benefits were only seen in a few patients.In general,the endpoints did not show significant improvements.This suggests that it will be helpful to learn more about the basic biology of this fascinating but complicated GDNF/RET signaling system in the dopaminergic midbrain and about recent developments in the field to facilitate its use in the clinic.Here we will refer to the latest publications and point out important open questions in the field.展开更多
胶质细胞系源性神经营养因子(glial cell line derived neurotrophic factor,GDNF)属于神经营养因子超家族,是TGF-β超家族的一个亚家族成员。目前已发现的GDNF家族配体(GDNF family ligand,GFL)有GDNF、neurturin(NRTN)、artemin(ARTN)...胶质细胞系源性神经营养因子(glial cell line derived neurotrophic factor,GDNF)属于神经营养因子超家族,是TGF-β超家族的一个亚家族成员。目前已发现的GDNF家族配体(GDNF family ligand,GFL)有GDNF、neurturin(NRTN)、artemin(ARTN)、persephin(PSPN)4个成员。GDNF家族受体为GFRα1-4,分别对应着GDNF家族配体GDNF、NRTN、ARTN及PSPN。通常GFRα通过糖基磷脂酰肌醇(glycosyl phosphatidyl inositol,GPI)锚着到细胞膜上,经GDNF家族配体刺激后募集受体酪氨酸激酶RET作为共受体并形成GFL/GFRα/RET复合物,使RET酪氨酸激酶磷酸化,进一步活化下游的Ras/MAPK、PI3K、PLCγ信号通路进而调控细胞的功能。最初对GDNF家族成员的功能研究主要集中在神经系统,发现GDNF/GFRα信号对中枢神经系统有特异的营养作用和促轴突生长作用,在参与促进神经元存活及轴突损伤修复等方面有其他生长因子不可比拟的作用。但随着研究的进展,越来越多的资料表明GDNF/GFRα信号在肿瘤的发生发展中也占据一席之地,尤其在促进肿瘤侵袭转移方面具有重要作用。本文聚焦GDNF/GFRα1信号,重点阐述GDNF/GFRα1信号在肿瘤进展和侵袭转移中的作用以及相关分子信号机制,以期为神经-内分泌-肿瘤相关性研究提供参考,为肿瘤的防治提供新的靶点和视角。展开更多
Objective:Because of the poor prognosis of lacrimal adenoid cystic carcinoma(LACC),we aimed to investigate the effects of perineural invasion(PNI)and consequent aberrations in GDNF/GFRα-1/RET protein expression on LA...Objective:Because of the poor prognosis of lacrimal adenoid cystic carcinoma(LACC),we aimed to investigate the effects of perineural invasion(PNI)and consequent aberrations in GDNF/GFRα-1/RET protein expression on LACC recurrence.Methods:Clinicopathological data for 51 histologically confirmed patients with LACC enrolled between 2001 and 2017 were retrospectively analyzed.Hematoxylin and eosin staining was applied to assess PNI.Tissue-based immunohistochemistry(IHC)detection of GDNF,GFRα-1,and RET proteins was performed on LACC formalin-fixed,paraffin-embedded specimens.We generated semi-quantitative data of the IHC results and compared them with the clinicopathological data for the 51 patients.Results:Of the 51 patients,19(37.3%)were PNI positive.Recurrence was more common for LACC with than without PNI(73.7%vs.37.5%,P=0.01).GDNF,GFRα-1,and RET proteins were expressed in 62.7%,62.7%,and 54.9%of the 51 patients with LACC,respectively.The expression of all 3 proteins was more common in patients with than without PNI.In agreement with previous findings,PNI-associated GFRα-1 and RET positivity,as detected by IHC,remained significantly associated with recurrence,whereas GDNF expression,as detected by IHC,was not correlated with LACC recurrence.Specifically,patients with concurrent GFRα-1 and RET expression may have a high risk of PNI(89.5%positivity rate)and recurrence(84.2%positivity rate).Conclusions:PNI may contribute to LACC recurrence.The concurrent expression of GFRα-1 and RET proteins,as detected by IHC,may potentially be associated with LACC PNI and recurrence.展开更多
文摘目的探讨有淋巴结转移和无淋巴结转移的乳腺癌组织中胶质细胞系源性神经营养因子受体α1(glial cell line derived neurotrophic factor α1,GFRα1)、RET原癌基因(RET proto-oncogene,RET)及神经细胞黏附分子(nerve cell adhesion molecule,NCAM)的表达水平,探索GFRα1可能的下游通路与淋巴结转移的关系。方法从乳腺癌患者中采用随机数字表法抽取有淋巴结转移和无淋巴结转移者各50例,分为淋巴结转移组和无淋巴结转移组,收集其组织标本和临床资料。采用免疫组织化学及Western blot法检测两组中GFRα1、RET及NCAM的表达水平,结合患者淋巴结状态进行分析。结果在免疫组织化学评分中GFRα1和RET在淋巴结转移组中的表达水平高于无淋巴结转移组[(3.967±1.847) vs (2.367±1.903),(3.967±1.752) vs (2.433±1.591),均P<0.05]。Western blot法显示,GFRα1和RET在淋巴结转移组中的蛋白表达水平高于无淋巴结转移组[(0.679±0.044) vs (0.495±0.064),(0.510±0.018) vs (0.291±0.035),均P<0.05]。免疫组织化学和Western blot法均显示,两组NCAM表达水平比较,差异无统计学意义(均P>0.05)。结论 GFRa1和RET在淋巴结转移乳腺癌患者的原发灶组织中的表达高于无淋巴结转移患者,可能与神经胶质细胞源性神经营养因子(glial cell line derived neurotrophic factor,GDNF)GDNF-GFRα1-RET通路的激活有关。
基金BRACE-Dementia Research,UK(ERK)Alzheimer’s Research UKthe Northcott Devon Medical Foundation(to JAC and ERK)for financial support。
文摘The neurotrophic signaling of glial cell line-derived neurotrophic factor(GDNF)with its canonical receptor,the receptor tyrosine kinase RET,coupled together with the GDNF family receptor alpha 1 is important for dopaminergic neuron survival and physiology in cell culture experiments and animal models.This prompted the idea to try GDNF/RET signaling as a therapeutic approach to treat Parkinson’s disease with the hallmark of dopaminergic cell death in the substantia nigra of the midbrain.Despite several clinical trials with GDNF in Parkinson’s disease patients,which mainly focused on optimizing the GDNF delivery technique,benefits were only seen in a few patients.In general,the endpoints did not show significant improvements.This suggests that it will be helpful to learn more about the basic biology of this fascinating but complicated GDNF/RET signaling system in the dopaminergic midbrain and about recent developments in the field to facilitate its use in the clinic.Here we will refer to the latest publications and point out important open questions in the field.
文摘胶质细胞系源性神经营养因子(glial cell line derived neurotrophic factor,GDNF)属于神经营养因子超家族,是TGF-β超家族的一个亚家族成员。目前已发现的GDNF家族配体(GDNF family ligand,GFL)有GDNF、neurturin(NRTN)、artemin(ARTN)、persephin(PSPN)4个成员。GDNF家族受体为GFRα1-4,分别对应着GDNF家族配体GDNF、NRTN、ARTN及PSPN。通常GFRα通过糖基磷脂酰肌醇(glycosyl phosphatidyl inositol,GPI)锚着到细胞膜上,经GDNF家族配体刺激后募集受体酪氨酸激酶RET作为共受体并形成GFL/GFRα/RET复合物,使RET酪氨酸激酶磷酸化,进一步活化下游的Ras/MAPK、PI3K、PLCγ信号通路进而调控细胞的功能。最初对GDNF家族成员的功能研究主要集中在神经系统,发现GDNF/GFRα信号对中枢神经系统有特异的营养作用和促轴突生长作用,在参与促进神经元存活及轴突损伤修复等方面有其他生长因子不可比拟的作用。但随着研究的进展,越来越多的资料表明GDNF/GFRα信号在肿瘤的发生发展中也占据一席之地,尤其在促进肿瘤侵袭转移方面具有重要作用。本文聚焦GDNF/GFRα1信号,重点阐述GDNF/GFRα1信号在肿瘤进展和侵袭转移中的作用以及相关分子信号机制,以期为神经-内分泌-肿瘤相关性研究提供参考,为肿瘤的防治提供新的靶点和视角。
文摘目的 :制备胶质细胞源性神经营养因子受体 α1(GFRα1)的突变体质粒 ,并建立 r GFRα1各突变体和 RET基因双转染的稳定 RCE细胞株。 方法 :通过 Fugene6脂质体转染试剂 ,将 PCR法快速制备的 pc DNA3- r GFRα1突变体质粒分别与带潮霉素 B抗性筛选标记的 pc DNA3.1- RET质粒共转染野生型 PC12细胞 ,建立 r GFRα1各突变体和 RET基因双转染的稳定PC12细胞株。经 Western印迹和细胞免疫荧光化学方法对转染入 PC12细胞中的各 r GFRα1突变体基因和 RET基因的表达进行鉴定。结果 :Western印迹和细胞免疫荧光化学方法检测均证实了所构建的细胞株中有转入基因的正确表达。结论 :成功构建了 r GFRα1各突变体基因和 RET基因同时转入表达的稳定细胞株 ,为研究 r GFRα1中关键氨基酸的位点参与胶质细胞源性神经营养因子 (GDNF)信号转导的作用奠定基础。
基金supported by the Tianjin Municipal Commission of Health and Family Planning Science Foundation Grant(Grant Nos.2015KZ100 and 2014KZ098)。
文摘Objective:Because of the poor prognosis of lacrimal adenoid cystic carcinoma(LACC),we aimed to investigate the effects of perineural invasion(PNI)and consequent aberrations in GDNF/GFRα-1/RET protein expression on LACC recurrence.Methods:Clinicopathological data for 51 histologically confirmed patients with LACC enrolled between 2001 and 2017 were retrospectively analyzed.Hematoxylin and eosin staining was applied to assess PNI.Tissue-based immunohistochemistry(IHC)detection of GDNF,GFRα-1,and RET proteins was performed on LACC formalin-fixed,paraffin-embedded specimens.We generated semi-quantitative data of the IHC results and compared them with the clinicopathological data for the 51 patients.Results:Of the 51 patients,19(37.3%)were PNI positive.Recurrence was more common for LACC with than without PNI(73.7%vs.37.5%,P=0.01).GDNF,GFRα-1,and RET proteins were expressed in 62.7%,62.7%,and 54.9%of the 51 patients with LACC,respectively.The expression of all 3 proteins was more common in patients with than without PNI.In agreement with previous findings,PNI-associated GFRα-1 and RET positivity,as detected by IHC,remained significantly associated with recurrence,whereas GDNF expression,as detected by IHC,was not correlated with LACC recurrence.Specifically,patients with concurrent GFRα-1 and RET expression may have a high risk of PNI(89.5%positivity rate)and recurrence(84.2%positivity rate).Conclusions:PNI may contribute to LACC recurrence.The concurrent expression of GFRα-1 and RET proteins,as detected by IHC,may potentially be associated with LACC PNI and recurrence.
