受体酪氨酸激酶家庭分子EphA3在前列腺癌进展中的作用研究
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摘要
前列腺癌是男性常发恶性肿瘤,占世界癌症总发病数的十分之一,每年约有20万患者死于前列腺癌,我国的发病率近年来呈逐年显著上升趋势。前列腺癌是雄激素依赖性肿瘤。Huggins因建立双侧睾丸切除手术治疗前列腺癌获诺贝尔奖,成为60多年来临床最常用的治疗方法。而随后发现,在术后12-36个月,不依赖雄激素的癌细胞生长导致病人死亡。至今临床治疗没有突破性进展。因此,阐明前列腺癌细胞生长的复杂分子机理,发现有效的诊断治疗方法,是目前亟待解决的科学问题。本课题旨在阐明受体酪氨酸激酶家族分子EphA3能否在前列腺癌进展中发挥作用,能否促进前列腺癌从雄激素依赖向雄激素非依赖的转变,并探索其发挥作用的分子机制,为发现新的前列腺癌相关信号转导途径,发现新的药物靶标和诊断治疗方法奠定基础。
从细胞、动物和临床三个水平,对EphA3在前列腺癌进展中的作用进行了研究。首先建立表达不同水平EphA3的前列腺癌细胞模型,分别筛选了野生型EphA3和胞内区磷酸化位点突变体3YF过表达的LNCaP和PC3细胞株以及RNAi敲降内源性EphA3的C4-2B稳定细胞株。在细胞水平通过MTT、平板克隆形成、软琼脂集落形成、纤粘连蛋白FN黏附生长实验和体外迁移实验,发现EphA3表达增强前列腺癌细胞的存活和恶性增殖能力,降低前列腺癌细胞在FN上的黏附生长能力,促进细胞的迁移和运动。将野生型EphA3和磷酸化位点突变体3YF过表达的LNCaP前列腺癌细胞系及对照细胞皮下接种裸鼠,发现两者均能够增强LNCaP细胞的体内成瘤能力。肿瘤组织切片HE染色发现,与对照组相比高表达组病理性核分裂象明显增多。进一步用包含有正常前列腺、前列腺良性增生和前列腺癌组织共110例临床标本的组织芯片检测EphA3的表达情况,结果发现,与正常前列腺组织相比,EphA3在前列腺癌组织中呈现高表达,尤其是在Gleason3级以上的标本中,呈现强阳性表达。将免疫组化的结果进行图像分析使EphA3表达量化,统计结果显示,EphA3表达量与前列腺癌Gleason分级呈正相关趋势。同时,随着前列腺癌级别的升高,EphA3的细胞定位发生改变。在Gleason1级中,EphA3主要表达于细胞浆中,Gleason2级和3级的标本胞浆和胞核中均有表达,Gleason4级主要呈细胞核阳性,而到了Gleason5级,EphA3蛋白浓缩聚集于细胞核。以上这些实验结果确定了EphA3的癌基因性质,其表达能够促进前列腺癌的进展。
进一步对EphA3是否能够促进前列腺癌从雄激素依赖向雄激素非依赖的转变进行了研究。用生理浓度雄激素处LNCaP细胞后,EphA3表达随雄激素水平降低而升高。雄激素受体拮抗剂Casodex处理条件下MTT实验发现,EphA3过表达降低LNCap细胞对Casodex的敏感性。为了研究这种耐药性是否是通过雄激素受体AR信号通路实现的,在撤除雄激素或者阻断AR的条件下,进行了软琼脂集落形成实验,发现在AR信号通路阻断情况下,EphA3仍能够增强前列腺癌细胞的恶性程度。荧光素酶实验分析了EphA3对外源性和内源性AR转录激活活性的影响,结果表明EphA3抑制AR的转录活性。神经内分泌分化(Neuroendocrine Differentiation,NED)现象在很多中晚期前列腺癌病灶中出现,且NED程度与前列腺癌的分级分期和复发成正相关。而NE细胞一般不表达AR,故前列腺癌细胞NED现象增强时,AR的表达和活性会降低。我们在筛选EphA3稳定表达细胞株时发现,EphA3高表达使LNCap细胞发生神经细胞样形态变化。进而在模拟雄激素去势条件下,发现在EphA3高表达的LNCaP细胞中,神经内分泌细胞的两个分子标志物嗜铬素A(CgA)和神经元特异性烯醇化酶(NSE)随雄激素去势培养时间的延长,呈现明显上升趋势,而对照中这种趋势并不明显。在另一种前列腺癌细胞C4-2B中将内源性EphA3表达敲降后,Western blot得到了与此一致的结果。这些结果初步解释了,EphA3促进前列腺癌细胞雄激素非依赖生长同时抑制了AR活性这一对看似矛盾的现象。
Akt信号通路在肿瘤发生过程中发挥重要的作用,能够促进细胞的增殖,抑制细胞凋亡,促进肿瘤血管生成,促进细胞侵袭和转移,最近的研究表明Akt还能促进前列腺癌细胞神经内分泌分化。本研究检测了EphA3表达对Akt信号通路的影响,发现EphA3可以增加Akt信号通路的三个分子Akt、GSK-3β和PDK1的磷酸化水平,激活Akt信号通路。胞外信号调节激酶ERK/MAPK居于调节细胞生长、发育及分裂的信号网络的枢纽位置,同时此通路的激活可增强雄激素撤除条件下前列腺癌细胞的神经内分泌分化现象。本研究结果显示,EphA3表达可以增加ERK的磷酸化水平,激活ERK信号通路。以上结果揭示了EphA3增强前列腺癌细胞存活和恶性增殖,促进前列腺癌神经内分泌分化的分子机制。
为了进一步探知EphA3发挥作用的分子机制,发现EphA3影响的未知分子和信号通路,我们分别用Affymetrix的基因表达谱芯片和免疫沉淀(IP)联合高解析离子淌度质谱(HDMS)对EphA3影响的基因表达和EphA3相互作用的蛋白进行了筛选。基因表达谱芯片结果显示,EphA3高表达可上调一些癌基因和细胞增殖相关基因的表达,并下调一些黏附和凋亡相关基因的表达。这与细胞和动物水平的实验结果一致。IP-HDMS结果发现,EphA3可能与信号转导、染色体结构维持、核酸结合和转运、蛋白质和糖类代谢相关的重要蛋白质相互作用。Co-IP实验验证EphA3能够与细胞骨架相关蛋白PT-WD体内相互作用。这些结果为揭示EphA3促进前列腺癌进展的分子机制提供了重要信息。
Prostate cancer(PCa) is a common malignant tumor in males and occupies 1/10 of the total tumor incident number all over the world.About 200,000 patients die of PCa each year.The incidence of PCa has been increasing in recent years in China. PCa is an androgen associated tumor.The surgery of PCa by removing the testes which led to a Nobel Prize for Huggins has been the most common clinical treatment for more than 60 years.But most tumors eventually become refractory to androgen ablation 12-36 months later.And there's no breakthrough in clinical treatment until now.So it's urgent to clarify the molecular mechanism of growth of PCa cells and find valid diagnostic and therapeutic methods.Our study is aimed to investigate whether EphA3,which is a member of RTK family,can play a role in PCa progression and whether it can promote the transition of PCa from androgen dependent stage to androgen independent stage as well as the mechanism of its function.
The function of EphA3 in PCa progression was studied in vitro,in vivo and at clinical levels.Firstly,PCa cell models with different expression levels of EphA3 were established including LNCaP and PC3 cell clones with overexpression of wild EphA3 or mutant EphA3 in which three tyrosines mutate to phenylalanines(3YF) and C4-2B cell clones with expression of endogenous EphA3 knocked down by RNAi.It was found that EphA3 could enhance the abilities of survival and malignant proliferation of PCa cells,reduce cell adhesion on FN and promote migration and motility of PCa cells through MTT,plate colony-formation assays,soft agar assays,FN adhesion and migration assays.Then LNCaP-EphA3,LNCaP-3YF and the control cells were subcutaneously inoculated to nude mice and both EphA3 and 3YF can improve tumorigenicity in vivo compared to control.Further,a tissue array with 110 clinical specimens including normal prostate,benign prostate hyperplasia(BPH) and prostate cancer tissues was selected to detect the expression of EphA3.Results of immunohistochemisty showed increase expressions of EphA3 in PCa tissues compared to normal and BPH tissues,especially in cases more advanced than gleason3.The results of immunohistochemisty were measured by quantitative image analysis and statistical results indicated positive correlation between expression of EphA3 and gleason grades of PCa.Simultaneously,cellular localization of EphA3 chaged as PCa gleason grades increased.EphA3 expressed preferentially in cytoplasm in gleasonl,equally in both cytoplasmic and nuclear portions in gleason2 and 3,predominantly as nuclear staining in gleason4 and nodularly in a cluster of cell nuclei in gleason5.All the data above identified that EphA3 is an oncogene and its expression can promote the progression of PCa.
Roles of EphA3 expression in the trasition of PCa from androgen dependent state to androgen independent stage were inspected next.Expression of EphA3 increased as androgen decreased when treated by physiological levels of androgen.When treated by casodex,an androgen receptor antagonist,EphA3 attenuated the sensitivity of LNCaP to the drug in MTT assay.To investigate whether the drug resistance was accomplished by AR pathway,soft agar assays with AR antagonist or without androgen were performed.Under these conditions EphA3 could still enhance the malignancy of PCa cells.Effects of EphA3 expression on transcriptional activity of ectogenesis and endogenous AR were evaluated by luciferase analysis and the results showed that EphA3 inhibited transcriptional activity of AR.Neuroendocrine differentiation(NED) is often detected in advanced PCa and degree of NED correlates positively with gleason grades and recurrence of PCa.However there is no AR expression in neuroendocrine cells,so expression and activity of AR decreases when NED enhances in PCa tissues.A nerve cell-like morphologic change was observed in EphA3 over-expressed LNCaP cells.In androgen castrate culturing,expression of CgA and NSE,the two markers of neuroendocrine cells,were found to increase obviously in EphA3 over-expressed LNCap rather than the control cells.And conformable results were detected using C4-2B with endogenous expression of EphA3 knocked down in western blot.These data can explain the paradox of EphA3 between the promotion of PCa progression and inhibition of AR activity.
Akt pathway plays an critical role in tumorigenesis,which can promote growth, angiogenesis,invasion and metastasis and can suppress apoptosis.Recently Akt is found to promote NED of PCa.In this study,influence of EphA3 expression on Akt pathway was detected and results showed that EphA3 activated Akt pathway by raising the phosphorylation level of Akt,GSK-3βand PDK1 which were three molecules included in Akt pathway.ERK/MAPK is the center of regulation networks of growth, development and division.Phosphorylation of ERK was also enhanced by EphA3 in our study.The results above revealed the molecular mechanism of EphA3 to promote survival and NED of PCa cells.
Affymetrix microarray of gene expression profile and IP combined with HDMS were used respectively to scan the changes of gene expression in LNCaP-EphA3 and interact proteins of EphA3.Data of microarray showed that some oncogenes and proliferation associated genes were up-regulated and some adhesion and apoptosis associated genes were down-regulated by EphA3.These results are accordant with data of cultured cells and mice.Scanning results in IP-HDMS showed that EphA3 may interact with important proteins associated with signaling,structural maintenance of chromosomes,nucleic acid binding and transport and metabolism of protein and carbohydrate.Using Co-IP,EphA3 was validated to interact with PT-WD1,a cytoskeleton protein.These data provided important information for revealing the molecular mechanism of the role of EphA3 in PCa progression.
从细胞、动物和临床三个水平,对EphA3在前列腺癌进展中的作用进行了研究。首先建立表达不同水平EphA3的前列腺癌细胞模型,分别筛选了野生型EphA3和胞内区磷酸化位点突变体3YF过表达的LNCaP和PC3细胞株以及RNAi敲降内源性EphA3的C4-2B稳定细胞株。在细胞水平通过MTT、平板克隆形成、软琼脂集落形成、纤粘连蛋白FN黏附生长实验和体外迁移实验,发现EphA3表达增强前列腺癌细胞的存活和恶性增殖能力,降低前列腺癌细胞在FN上的黏附生长能力,促进细胞的迁移和运动。将野生型EphA3和磷酸化位点突变体3YF过表达的LNCaP前列腺癌细胞系及对照细胞皮下接种裸鼠,发现两者均能够增强LNCaP细胞的体内成瘤能力。肿瘤组织切片HE染色发现,与对照组相比高表达组病理性核分裂象明显增多。进一步用包含有正常前列腺、前列腺良性增生和前列腺癌组织共110例临床标本的组织芯片检测EphA3的表达情况,结果发现,与正常前列腺组织相比,EphA3在前列腺癌组织中呈现高表达,尤其是在Gleason3级以上的标本中,呈现强阳性表达。将免疫组化的结果进行图像分析使EphA3表达量化,统计结果显示,EphA3表达量与前列腺癌Gleason分级呈正相关趋势。同时,随着前列腺癌级别的升高,EphA3的细胞定位发生改变。在Gleason1级中,EphA3主要表达于细胞浆中,Gleason2级和3级的标本胞浆和胞核中均有表达,Gleason4级主要呈细胞核阳性,而到了Gleason5级,EphA3蛋白浓缩聚集于细胞核。以上这些实验结果确定了EphA3的癌基因性质,其表达能够促进前列腺癌的进展。
进一步对EphA3是否能够促进前列腺癌从雄激素依赖向雄激素非依赖的转变进行了研究。用生理浓度雄激素处LNCaP细胞后,EphA3表达随雄激素水平降低而升高。雄激素受体拮抗剂Casodex处理条件下MTT实验发现,EphA3过表达降低LNCap细胞对Casodex的敏感性。为了研究这种耐药性是否是通过雄激素受体AR信号通路实现的,在撤除雄激素或者阻断AR的条件下,进行了软琼脂集落形成实验,发现在AR信号通路阻断情况下,EphA3仍能够增强前列腺癌细胞的恶性程度。荧光素酶实验分析了EphA3对外源性和内源性AR转录激活活性的影响,结果表明EphA3抑制AR的转录活性。神经内分泌分化(Neuroendocrine Differentiation,NED)现象在很多中晚期前列腺癌病灶中出现,且NED程度与前列腺癌的分级分期和复发成正相关。而NE细胞一般不表达AR,故前列腺癌细胞NED现象增强时,AR的表达和活性会降低。我们在筛选EphA3稳定表达细胞株时发现,EphA3高表达使LNCap细胞发生神经细胞样形态变化。进而在模拟雄激素去势条件下,发现在EphA3高表达的LNCaP细胞中,神经内分泌细胞的两个分子标志物嗜铬素A(CgA)和神经元特异性烯醇化酶(NSE)随雄激素去势培养时间的延长,呈现明显上升趋势,而对照中这种趋势并不明显。在另一种前列腺癌细胞C4-2B中将内源性EphA3表达敲降后,Western blot得到了与此一致的结果。这些结果初步解释了,EphA3促进前列腺癌细胞雄激素非依赖生长同时抑制了AR活性这一对看似矛盾的现象。
Akt信号通路在肿瘤发生过程中发挥重要的作用,能够促进细胞的增殖,抑制细胞凋亡,促进肿瘤血管生成,促进细胞侵袭和转移,最近的研究表明Akt还能促进前列腺癌细胞神经内分泌分化。本研究检测了EphA3表达对Akt信号通路的影响,发现EphA3可以增加Akt信号通路的三个分子Akt、GSK-3β和PDK1的磷酸化水平,激活Akt信号通路。胞外信号调节激酶ERK/MAPK居于调节细胞生长、发育及分裂的信号网络的枢纽位置,同时此通路的激活可增强雄激素撤除条件下前列腺癌细胞的神经内分泌分化现象。本研究结果显示,EphA3表达可以增加ERK的磷酸化水平,激活ERK信号通路。以上结果揭示了EphA3增强前列腺癌细胞存活和恶性增殖,促进前列腺癌神经内分泌分化的分子机制。
为了进一步探知EphA3发挥作用的分子机制,发现EphA3影响的未知分子和信号通路,我们分别用Affymetrix的基因表达谱芯片和免疫沉淀(IP)联合高解析离子淌度质谱(HDMS)对EphA3影响的基因表达和EphA3相互作用的蛋白进行了筛选。基因表达谱芯片结果显示,EphA3高表达可上调一些癌基因和细胞增殖相关基因的表达,并下调一些黏附和凋亡相关基因的表达。这与细胞和动物水平的实验结果一致。IP-HDMS结果发现,EphA3可能与信号转导、染色体结构维持、核酸结合和转运、蛋白质和糖类代谢相关的重要蛋白质相互作用。Co-IP实验验证EphA3能够与细胞骨架相关蛋白PT-WD体内相互作用。这些结果为揭示EphA3促进前列腺癌进展的分子机制提供了重要信息。
Prostate cancer(PCa) is a common malignant tumor in males and occupies 1/10 of the total tumor incident number all over the world.About 200,000 patients die of PCa each year.The incidence of PCa has been increasing in recent years in China. PCa is an androgen associated tumor.The surgery of PCa by removing the testes which led to a Nobel Prize for Huggins has been the most common clinical treatment for more than 60 years.But most tumors eventually become refractory to androgen ablation 12-36 months later.And there's no breakthrough in clinical treatment until now.So it's urgent to clarify the molecular mechanism of growth of PCa cells and find valid diagnostic and therapeutic methods.Our study is aimed to investigate whether EphA3,which is a member of RTK family,can play a role in PCa progression and whether it can promote the transition of PCa from androgen dependent stage to androgen independent stage as well as the mechanism of its function.
The function of EphA3 in PCa progression was studied in vitro,in vivo and at clinical levels.Firstly,PCa cell models with different expression levels of EphA3 were established including LNCaP and PC3 cell clones with overexpression of wild EphA3 or mutant EphA3 in which three tyrosines mutate to phenylalanines(3YF) and C4-2B cell clones with expression of endogenous EphA3 knocked down by RNAi.It was found that EphA3 could enhance the abilities of survival and malignant proliferation of PCa cells,reduce cell adhesion on FN and promote migration and motility of PCa cells through MTT,plate colony-formation assays,soft agar assays,FN adhesion and migration assays.Then LNCaP-EphA3,LNCaP-3YF and the control cells were subcutaneously inoculated to nude mice and both EphA3 and 3YF can improve tumorigenicity in vivo compared to control.Further,a tissue array with 110 clinical specimens including normal prostate,benign prostate hyperplasia(BPH) and prostate cancer tissues was selected to detect the expression of EphA3.Results of immunohistochemisty showed increase expressions of EphA3 in PCa tissues compared to normal and BPH tissues,especially in cases more advanced than gleason3.The results of immunohistochemisty were measured by quantitative image analysis and statistical results indicated positive correlation between expression of EphA3 and gleason grades of PCa.Simultaneously,cellular localization of EphA3 chaged as PCa gleason grades increased.EphA3 expressed preferentially in cytoplasm in gleasonl,equally in both cytoplasmic and nuclear portions in gleason2 and 3,predominantly as nuclear staining in gleason4 and nodularly in a cluster of cell nuclei in gleason5.All the data above identified that EphA3 is an oncogene and its expression can promote the progression of PCa.
Roles of EphA3 expression in the trasition of PCa from androgen dependent state to androgen independent stage were inspected next.Expression of EphA3 increased as androgen decreased when treated by physiological levels of androgen.When treated by casodex,an androgen receptor antagonist,EphA3 attenuated the sensitivity of LNCaP to the drug in MTT assay.To investigate whether the drug resistance was accomplished by AR pathway,soft agar assays with AR antagonist or without androgen were performed.Under these conditions EphA3 could still enhance the malignancy of PCa cells.Effects of EphA3 expression on transcriptional activity of ectogenesis and endogenous AR were evaluated by luciferase analysis and the results showed that EphA3 inhibited transcriptional activity of AR.Neuroendocrine differentiation(NED) is often detected in advanced PCa and degree of NED correlates positively with gleason grades and recurrence of PCa.However there is no AR expression in neuroendocrine cells,so expression and activity of AR decreases when NED enhances in PCa tissues.A nerve cell-like morphologic change was observed in EphA3 over-expressed LNCaP cells.In androgen castrate culturing,expression of CgA and NSE,the two markers of neuroendocrine cells,were found to increase obviously in EphA3 over-expressed LNCap rather than the control cells.And conformable results were detected using C4-2B with endogenous expression of EphA3 knocked down in western blot.These data can explain the paradox of EphA3 between the promotion of PCa progression and inhibition of AR activity.
Akt pathway plays an critical role in tumorigenesis,which can promote growth, angiogenesis,invasion and metastasis and can suppress apoptosis.Recently Akt is found to promote NED of PCa.In this study,influence of EphA3 expression on Akt pathway was detected and results showed that EphA3 activated Akt pathway by raising the phosphorylation level of Akt,GSK-3βand PDK1 which were three molecules included in Akt pathway.ERK/MAPK is the center of regulation networks of growth, development and division.Phosphorylation of ERK was also enhanced by EphA3 in our study.The results above revealed the molecular mechanism of EphA3 to promote survival and NED of PCa cells.
Affymetrix microarray of gene expression profile and IP combined with HDMS were used respectively to scan the changes of gene expression in LNCaP-EphA3 and interact proteins of EphA3.Data of microarray showed that some oncogenes and proliferation associated genes were up-regulated and some adhesion and apoptosis associated genes were down-regulated by EphA3.These results are accordant with data of cultured cells and mice.Scanning results in IP-HDMS showed that EphA3 may interact with important proteins associated with signaling,structural maintenance of chromosomes,nucleic acid binding and transport and metabolism of protein and carbohydrate.Using Co-IP,EphA3 was validated to interact with PT-WD1,a cytoskeleton protein.These data provided important information for revealing the molecular mechanism of the role of EphA3 in PCa progression.
引文
1.Gronberg H.Prostate cancer epidemiology.Lancet 2003;361(9360):859-64.
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