雄激素受体与激素非依赖性前列腺癌

晚期前列腺癌可发生激素非依赖,对抗雄激素治疗不再有效。前列腺癌对雄激素依赖性发生变化的机制目前尚未阐明,近年来的研究显示前列腺癌雄激素非依赖性与雄激素受体(AR)的反常激活有关,与雄激素受体(AR)表达增加和突变、AR调节因子表达改变有关,细胞因子IL-6、IL-4,糖原合成激酶-3β参与激素非依赖性前列腺癌的AR激活。本文就这方面的研究进展作一综述。     

雄激素受体与激素非依赖性前列腺癌

晚期前列腺癌可发生激素非依赖，对抗雄激素治疗不再有效。前列腺癌对雄激素依赖性发生变化的机制目前尚未阐明，近年来的研究显示前列腺癌雄激素非依赖性与雄激素受体(AR)的反常激活有关，与雄激素受体(AR)表达增加和突变、AR调节因子表达改变有关，细胞因子IL-6、IL-4，糖原合成激酶-3β参与激素非依赖性前列腺癌的AR激活。本文就这方面的研究进展作一综述。     

雄激素受体在雄激素非依赖性前列腺癌的表达

目的探讨雄激素受体(AR)在国人雄激素非依赖性前列腺癌(AIPC)的表达及其临床意义。方法采用免疫组化两步法,检测AR在15例AIPC和20例雄激素依赖性前列腺癌(ADPC)组织标本的表达水平。结果1例AIPC无AR表达,其余14例AIPC及全部ADPC均有AR高表达,AIPC染色的光密值为0.31±0.04较ADPC0.28±0.03升高。结论大多数国人AIPC均高表达AR,AR的异常表达可能在前列腺癌的进展中发挥重要的作用。     

HER-2/neu与雄激素非依赖性前列腺癌

前列腺癌开始时属于雄激素依赖性，在接受药物或手术睾丸去势治疗后肿瘤退缩，但最终还是会转变为雄激素非依赖性而继续生长。研究发现多数雄激素非依赖性前列腺癌持续表达雄激素受体(AR)和雄激素依赖性基因前列腺特异性抗原(PSA)，这说明尽管已处于睾酮去势水平，这些细胞中仍保持着AR信号通路。现有的解释是，AR激素结合区的扩增或突变改变了AR的结合功能，     

雄激素非依赖性前列腺癌分子机理研究进展

前列腺癌分激素依赖和激素非依赖2类。激素非依赖性前列腺癌治疗非常困难。目前,有很多学说解释其发生机理,我们对近年雄激素受体(AR)机理综述如下。一、克隆选择(clonal selection)前列腺癌从激素依赖转化为激素非依赖性“克隆选择”学说认为:前列腺上皮是由雄性激素非依赖性基底干细胞,雄性激素依赖性分泌腔细胞和雄性激素敏感性过渡细胞构成。正常的雄激素环境决定正常前列腺基底细胞生长成为分泌性腔细胞,这种平衡的稳态是维持前列腺生长而不会过度增生的重要条件。前列腺的这种稳态一旦被破坏,可导致正常前列腺基底细胞、分泌腔细胞过度增生。前列腺内稳态不平衡通常是多位点和多基因源的。Bostwick等发现同一前列腺多部位腺上皮内瘤(PIN),并且在同一切除前列腺标本中发现由不同遗传物资引起的多中心瘤。证实在治疗前,前列腺癌由不同激素敏感细胞构成[1]。二、雄激素受体机制雄激素非依赖性前列腺癌的机制是通过雄激素受体依赖和受体非依赖实现的(图1)[2]。大多数雄激素非依赖性前列腺癌表达AR。当雄激素被剥夺时,AR激活至少有3种机制:由于基因扩增导致过度表达;其他激活剂而非雄激素的交叉激活;受体的特异性发生改变,与其他配体结...     

雄激素受体辅助因子与前列腺癌雄激素非依赖性的关系

前列腺癌是西方国家最常见的恶性肿瘤，是引起老年男性死亡的第二位原因。我国的前列腺发病率远低于欧美国家，但近年来有上升趋势。目前雄激素去势或者阻断仍然是晚期前列腺癌患者的首选治疗，然而，经这种治疗12～16个月后，前列腺癌由激素依赖性变成激素非依赖性，对抗雄激素治疗不再有效。尽管前列腺癌雄激素依赖性发生变化的机制目前尚不完全清楚，但大量的研究表明，前列腺癌雄激素非依赖性与雄激素受体(AR)的反常激活有关。     

鸟苷酸结合蛋白偶联受体(GPCR)与雄激素非依赖性前列腺癌

前列腺癌开始时属于雄激素依赖性,在接受药物或手术睾丸去势治疗后肿瘤退缩,但最终还是会转变为雄激素非依赖性而继续生长。现有的解释是:雄激素受体(AR)激素结合区的扩增或突变改变了AR的结合功能,比如AR突变后能够与雌二醇结合。AR也可以以配基非依赖方式被胰岛素样生长因子-1(IGF-1)、表皮生长因子(EGF)和角化生长因子(KGF)所激活。 前列腺癌是明显的多因性疾病,病程表现不一,     

非依赖雄激素的前列腺癌细胞株中雄激素受体的表达

几乎所有建立的前列腺癌细胞株均为雄激素非依赖性的,包括常用的表达雄激素受体(AR)阳性的LNCaP株和雄激素受体阴性的Du145和PC-3细胞株。作者试图找出这些细胞株不依赖雄激素的机制。作者应用基因分析方法检查LNCaP,CWR22R,PC-3,DU145和CA7T2CL细胞株中的AR启动子功能,并用Southern印记杂交,重亚硫酸盐转     

雄激素非依赖型前列腺癌中雄激素受体特征改变的研究进展

前列腺癌在欧美国家高龄男性中发病率较高,在我国的发病率近年来也有明显的上升趋势.雄激素在前列腺癌细胞的生长、转移中起决定性作用,雄激素只有和雄激素受体( androgen receptor,AR)相结合才能发挥作用.在前列腺癌发病前期,肿瘤细胞多为雄激素依赖型,去势治疗有一定疗效.但随着治疗时间延长,部分患者可转变为雄激素非依赖前列腺癌( androgen-independent prostate cancer,AIPC).研究AIPC中AR的相关改变可以帮助我们进一步探索AIPC的成因,为临床治疗提供思路.现就AIPC中与AR相关改变综述如下.     

熊果酸对前列腺癌细胞雄激素非依赖性的逆转作用

目的 探讨中药成分熊果酸对雄激素非依赖性前列腺癌(AIPC)的治疗作用及其机制.方法 应用熊果酸处理体外培养的人雄激素依赖性前列腺癌(ADPC)细胞株LNCaP和AIPC细胞株DU145,噻唑蓝(MTT)比色法检测细胞活性及对人工合成雄激素R1881的反应性,免疫细胞化学检测熊果酸对雄激素受体(AR)、糖皮质激素受体(GR)、前列腺特异性抗原(PSA)及成活因子HSP90和白细胞介素(IL)-6表达的影响,逆转录.聚合酶链反应(RT-PCR)检测熊果酸对DU145细胞AR mRNA表达的影响.结果 熊果酸对不同浓度雄激素下的LNCaP细胞均呈浓度和时间依赖性生长抑制,20 mg/L的熊果酸作用96 h对LNCaP细胞的抑制率近50%.0.1 nmoL/L的R1881为最适生长浓度,熊果酸作用后,LNCaP细胞生长的最适雄激素浓度上升了10倍;熊果酸对DU145细胞的生长有浓度和时间依赖性抑制效应,DU145细胞对AR阻断剂羟氟他胺缺乏反应,熊果酸作用同时再应用氟他胺比单纯熊果酸的作用更明显,对细胞抑制率明显上升.熊果酸作用后,LNCaP和DUl45细胞IL-6、HSF90表达均明显下降(P＜0.05),DU145细胞GR表达明显降低(P＜0.01),AR和PSA蛋白及AR mRNA出现再表达.结论 熊果酸能改善前列腺癌细胞对雄激素的反应性,使LNCaP细胞对雄激素的依赖性加强,并诱发了DU145细胞对雄激素的反应性,其部分机制是降低了GR、HSP90、IL-6的表达并促进AR再表达.     

Partial androgen insensitivity syndrome with thermolability in the androgen receptor

We report case of partial androgen insensitivity syndrome in a 12-year-old boy referred to our clinic complaining of bilateral gynecomastia and left undescended testicle. Laparoscopy for undescended testicle and bilateral mastectomy were performed, and the left testicle was absent. When skin fibroblasts of the scrotum obtained during surgery were cultured to analyse the androgen receptors, a slight thermolability was observed. Genomic examination of the androgen receptor gene could not detect any mutations.     

Gleason score predicts androgen independent progression after androgen deprivation therapy

OBJECTIVE: The Gleason system is the most widely utilized histologic grading system for prostate cancer and a powerful predictor of cancer behavior. In this study, we evaluated the prognostic value of the Gleason grading system in predicting progression to androgen independent prostate cancer (AIPC). METHODS: Records from 150 patients with advanced or metastatic prostate cancer treated with androgen deprivation therapy (ADT) were retrospectively reviewed. Androgen independent progression was defined as two consecutive elevations of serum prostate specific antigen (PSA) above the nadir value. Kaplan-Meier and the Cox proportional hazards methods were used to assess potential predictors of progression to AIPC. RESULTS: Patients with low and moderate Gleason scores experienced significantly longer remissions compared to those with Gleason score of 8-10 (p=0.0006, Log-Rank test). The cumulative hazard of progressing to AIPC increased by almost 70% for each unit increase in total Gleason score. CONCLUSION: In this patient cohort the Gleason score was the only independent predictor of progression to AIPC.     

Novel androgen receptor gene mutation in patient with complete androgen insensitivity syndrome

To present a rare case of a patient probably with complete androgen insensitivity syndrome (CAIS) and studied its potential genetic cause. A 24-year-old woman with a normal-appearing vulva and vagina presented to us because of primary amenorrhea. Imaging studies showed no uterus or ovary development but inguinal cryptorchism. Histopathologic examination revealed normal testicular structures. Sequencing the CAIS-associated androgen receptor gene revealed a novel missense mutation of T to G (F698L). A novel androgen receptor gene mutation in the ligand binding domain was detected in the present patient with CAIS, supporting the important role of an androgen receptor defect in the etiology of CAIS.     

雄激素的代谢作用

睾丸分泌的雄激素中最重要的是睾酮 ,睾酮对胚胎时期生殖导管和尿生殖窦的分化、精子发生、第二性征的发育和维持、青春期身体的直线生长、性功能以及对下丘脑 -垂体的反馈调节等均起着关键性作用。近年来对睾酮在非性器官的生理性和病理性作用产生了兴趣 ,随着科学技术的进步、经济状况的改善和人均寿命的提高 ,心血管疾病和糖尿病等代谢性疾病已成为人类的主要杀手 ,因此 ,对雄激素代谢作用的关注也在情理之中 ,现将近几年关于雄激素代谢作用的研究成果介绍如下。雄激素的蛋白代谢作用自 Kenyon等 ( 1 940 )用丙酸睾酮治疗睾丸功能减退成…     

Risks of androgen therapy

Elderly men with clinical and laboratory evidence of androgen deficiency are eligible for testosterone treatment.

With proper monitoring this is acceptably safe.

In the first year of testosterone treatment there should be a digital rectal examination of the prostate and measurement of prostate specific antigen every three months, thereafter yearly.

The rate of increase of prostate specific antigen (PSA) levels is more significant than its absolute values.

Levels of haemoglobin and the haematocrit should be monitored.     

Duration of androgen deprivation therapy with maximum androgen blockade for localized prostate cancer

Background

In this study, by comparing TVT surgery and TOT surgery for stress urinary incontinence in women, the characteristics and learning curves of both operative methods were studied.

Methods

A total of 83 women with stress urinary incontinence treated with tension-free vaginal tape (TVT) (n = 38) or transobturator tape (TOT) (n = 45) at Saiseikai Central Hospital between April 2004 and September 2009 were included. We compare the outcomes and learning curves between TVT surgery and TOT surgery. In statistical analysis, Student's t test, Fisher's exact test, and Mann-Whitney's U test were used.

Results

The surgical durations were 37.4 ± 15.7 minutes with TVT surgery and 31.0 ± 8.3 minutes with TOT surgery. A longer period of time was required for TVT surgery (p = 0.025). The residual urine at post-operative day 1 was higher in TVT surgery (25.9 ± 44.2 ml) than in TOT surgery (10.6 ± 19.2 ml) (p = 0.0452). The surgical duration of TVT surgery was shortened after the operator had performed 15 operations (p = 0.019).

Conclusions

In comparison of TVT surgery and TOT surgery, the surgical duration of TVT surgery was longer and the residual urine of TVT surgery was higher at post-operative day 1. Surgical experience could shorten the duration of TVT surgery.     

Purification of the human prostate androgen receptor. III. Purification of the androgen receptor and characterization of the purified androgen receptor

With 855 g of benign prostatic hypertrophic tissue as starting material, the androgen receptor (AR) was purified by combining the affinity chromatography of heparin Sepharose CL-6B and of R1881-carboxymethyloxime-albumin Sepharose 4B. The final purificationfraction had high-affinity, low-capacity binding to 3H-R1881 in the presence of 1,000-fold molar excess of triamicinolone acetonide (TA) with a dissociation constant of 2.4 nM. When the relative binding affinity was being assessed, the binding of the final purification fraction to 3H-R 1881 was not suppressed by estradiol or TA and revealed the binding specificity of the AR. Polyacrylamide gel electrophoresis showed no albumin or TeBG mixed in the final purification fraction. These results give evidence that the AR had been purified and that, in comparison with the original cytosol, the degree of purification was approximately 2,360 fold. The molecular weight of the purified AR was 32,000 as calculated by high performance liquid chromatography. The fact the antiserum from rabbit immunized with the purified AR showed a reaction against the purified AR leads us to believe that antibodies for the AR were successfully produced. Further immunological study on AR measurement is considered to be of great importance.