摘要
背景：
前列腺癌是欧美国家最常见的男性恶性肿瘤之一,是男性癌症死因的第二位。我国前列腺癌发病率虽然远低于西方国家,但近来随着人口老龄化及生活条件的改善,发病率呈逐年上升趋势。目前,前列腺癌早期均采用雄激素剥夺治疗且疗效满意。因为前列腺癌的生长、进展的最初阶段均有雄激素依赖性的特性,但经过一段时间的雄激素剥夺治疗后,几乎所有前列腺癌将转变为雄激素非依赖性前列腺癌(androgen-independent prostate cancer, AIPC)。AIPC的形成机制目前尚未阐明,缺乏有效治疗手段,一般均是应用放疗和化疗,患者的预后较差。
早期生长反应因子1(Early growth response gene-1 Egr1)是一种锌指样转录因子,为多基因转录因子家族(Egr1-4)中的一员。Egr1具有组织特异性,因为在乳腺癌,肺癌,神经系统肿瘤中Egr1均不表达,Egr1在正常前列腺组织中不表达或低表达,在前列腺癌组织中高表达。目前研究证明Egr1与前列腺癌的形成、进展、转移及预后密切相关。前列腺癌细胞中Egr1过表达能上调一系列生长因子,如胰岛素样生长因子Ⅱ(insulin-like growth factor-Ⅱ),转化生长因子β1(transforming growth factor-β1)和血小板衍生因子A(platelet-derived growth factor-A)。Egr1在前列腺癌的形成中起到如此重要的作用,其在前列腺癌向激素非依赖转化中是否也起到了关键作用。前列腺癌向激素非依赖转化过程中,分化抑制因子1(Id1)起到了重要的作用,高表达的Egr1是否也会上调Id1。Egr1是否也是前列腺癌雄激素非依赖性进展的重要分子生物学标记。
目的：
探讨Egr1在激素非依赖前列腺癌形成中的作用机制,Egr1和雄激素受体之间的关系,以及Egr1介导Id1促进激素依赖前列腺癌向激素非依赖转化中的作用。
研究方法：
对比临床24例激素依赖前列腺癌和5例激素非依赖前列腺癌组织标本中Egr1表达水平。体外模拟临床前列腺癌的治疗过程,给予雄激素剥夺培养前列腺癌细胞,观察Egr1表达水平的变化。前列腺癌细胞给予双氢睾酮和氟他胺刺激后,观察两组细胞内Egr1表达水平的变化,向PC3转染雄激素受体,重复以上实验。两组细胞均给予蛙皮素(Bombesin),观察Egr1和Id1表达水平的变化。24例激素依赖前列腺癌中,不同Gleason评分之间中Egr1及Id的表达趋势。
结果：
1、24例激素依赖前列腺癌与5例激素非依赖前列腺癌进行对比：5例激素非依赖前列腺癌均为强阳性(+++),24例中11例弱阳性为(+),9例为阳性(++),4例为强阳性(+++)。两组之间存在差异(P=0.003)。
2、前列腺癌两种细胞株(LNCaP和PC3)Egr1表达水平进行比较：mRNA水平上PC3为LNCaP的54倍,这和Westblot结果一致。体外前列腺癌细胞株LNCaP和PC3细胞均给予雄激素剥夺培养1-4天。LNCaP细胞株中,在mRNA及蛋白水平,Egr1在雄激素剥夺后均出现明显的上升趋势,PC3细胞株,雄激素剥夺后Egrl无明显变化。
3、在含有雄激素受体的雄激素敏感的前列腺癌LNCaP细胞中,双氢睾酮抑制Egrl表达,氟他胺增加Egrl表达,两者均称剂量依赖性。而在不含雄激素受体的前列腺癌PC3细胞中,雄激素剥夺后其Egrl表达水平并无明显变化,给予双氢睾酮和氟他胺后,Egrl表达无变化。但是向PC3前列腺癌细胞株内转染了人类全长雄激素受体后,再次给予双氢睾酮和氟他胺后,PC3细胞则表现为与LNCaP细胞相同的现象。
4、前列腺癌细胞株LNCaP和PC3中,蛙皮素(Bombesin, Egr1激动剂)在mRNA水平和蛋白水平均能明显上调Egr1和Id1的表达,并呈剂量依赖性。在24例前列腺癌组织标本中,根据Gleason评分不同分为三组(A组<7分,B组=7,C组>7分),其中A组与C组之间Egr1和Id1差异有统计学意义(Egr1组P：0.025,Id1组P=0.005)。
结论：
Egrl在雄激素非依赖前列腺癌明显高表达。在激素依赖前列腺癌中,雄激素剥夺会使Egr1表达逐渐增高,雄激素依赖性前列腺癌中雄激素通过其受体对Egr1进行负性调控,雄激素剥夺后Egr1逐渐增高介导的Id1高表达对前列腺癌向激素非依赖转化起到重要作用。
Background:
Prostate carcinoma (PCa) is one of the most common malignances in United States and Europe, which was the second cause for males death. Although the incidence of prostate cancer was low in our country, but in recently years confirmed PCa is getting higher and higher in China today with the aging and the diet habit changing. Androgen deprivation therapy (ADT) is generally employed for the treatment of advanced or metastatic prostate cancer, because the growth and progression of prostate cancer are initially androgen-dependent. However, the prostate cancer eventually progresses from an androgen-dependent to an aggressive androgen-independent stage, when it shows poor response to any anti-cancer therapy. It is not clear the mechanism of AIPC informed.It is lack of effective treatment when the prostate cancer change to androgen-independent prostate cancer. The patient's prognosis is poor, when radiation and chemotherapy is applied.
The early growth response gene 1 (Egr1) is a zinc finger transcription factor that belongs to a multigene family that includes Egr2, Egr3, Egr4. This is significant and specific to prostate tumor cells because in mammary, lung and glial tumors, Egr1, is not over-expressed but is low or absent. Egr1 is overexpressed in human prostate tumors but is low in or absent from normal prostate tissue. The level of Egr1 expression was found be correlated with PCa malignancy, progression, metastasis and prognosis. It was found that overexpression of Egr1 could be upregulated insulin-like growth factor-Ⅱ, transforming growth factor-β1 and platelet-derived growth factor-A.Egr1 was so very important in PCa informed, it maybe also play important role in androgen-independ prostate cancer informed. Id-1 was contribute to androgen-independ prostate cancer informed. Was overexpression Egr1 will upregulated Id1 expression,or Egrl protein may serve as an important molecular marker of androgen independent progression of PCa.
Objective:
The mechanism of Egr1 in the androgen-independent prostate cancer formation, the relationship between the androgen receptor and Egr1. Egr1 could be promote androgen-dependent prostate cancer changed to androgen-independent transformation mediated through Id.
Methods:
Expression of Egr1 were compared in 24 cases of androgen-dependent prostate cancer and 5 cases of androgen-independent prostate cancer. In vitro to mime of the clinical treatment for prostate cancer, the level of Egrl were observed in androgen deprivation in prostate cancer cells. Prostate cancer cells were treated by dihydrotestosterone and flutamide, the level of Egr1 were observed. Repeat the above experiment when PC3 transfected with androgen receptor. The level of Egr1 and Id1 were observation when prostate cancer cells were treated with Bombesin. The trend of Egr1 and Id were observed among different Gleason score in 24 cases of androgen-dependent prostate cancer.
Results:
1.24 cases of androgen-dependent prostate cancer and 5 cases of androgen-independent prostate cancer were compared. Five cases of androgen-independent prostate cancer were strongly positive (+++), from 24 cases androgen-dependent prostate cancer,11 cases of weak positive of (+),9 cases were positive (++),4 cases of strong positive (+++) (P=0.003).
2. Egr1 in PC3 cells was about 54 times than LNCaP cells, which was consisted with Westblot result. Prostate cancer cell line LNCaP and PC3 cells were under androgen deprivation for 1-4 days in vitro. Egr1 level was increased after androgen deprivation in the mRNA and protein levels in LNCaP cell lines. Egr1 level was no significant change after androgen deprivation in the mRNA and protein levels in PC3 cell line.
3. In androgen sensitive LNCaP cells which contained androgen receptor, dihydrotestosterone inhibited Egr1 expression, while flutamide increased Egr1 expression, both in a dose-dependent manner. While no statistically significant difference was found in Egr1 expression in AR-negative PC-3 cells in the same circumstance. When androgen receptor was introduced into PC-3 cells, PC3 was showed the same phenomenon during dihydrotestosterone and flutamide used as found in LNCaP.
4. Bombesin (Bombesin, Egr1 agonist) can be significantly up-regulated Egr1 and Id1 expression in mRNA level and protein level in LNCaP and PC3 cells in a dose-dependent manner. In the 24 cases of prostate cancer tissue samples, according to Gleason score were divided into three groups (group A<7, group B=7, group C>7), in which A group and C group between Egr1 and Id1 differences in statistical significance (Egr1 P=0.025, Id1 P=0.005)。
Conclusion:
Egr1 was significantly higher expression in androgen-independent prostate cancer. In the androgen-dependent prostate cancer, Egr1 expression was gradually increased after androgen deprivation. Egr1 expression in androgen dependent prostate cancer was negatively regulated by androgen in a receptor-dependent way. Increased Egr1 was mediated high expression of Id1 after androgen deprivation, which might contribute to emergence of androgen- independend prostate cancer.
引文
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