前列腺癌非编码RNA1在雄激素非依赖去势抵抗型前列腺癌细胞中的作用

目的 探讨长链非编码RNA前列腺癌非编码RNA1(PRNCR1)在雄激素非依赖的前列腺癌细胞中的作用.方法 应用实时定量PCR(qRT-PCR)检测雄激素依赖的前列腺癌细胞LNCaP及雄激素非依赖的前列腺癌细胞C4-2中PRNCR1的表达情况,通过RNA干扰技术沉默C4-2细胞中的PRNCR1,Western blot技术检测C4-2细胞中雄激素受体(AR)的表达变化,流式细胞术检测细胞凋亡的变化,MTT实验检测沉默PRNCR1表达对细胞增殖的影响,Transwell侵袭实验检测细胞侵袭能力的变化.结果 PRNCR1在雄激素非依赖的细胞系C4-2中高表达,干扰其表达可以明显降低前列腺癌细胞中AR的表达,抑制前列腺癌细胞的细胞增殖及细胞的侵袭能力,并促进细胞的凋亡.结论 PRNCR1介导AR在前列腺癌去势抵抗中发挥着重要作用.     

雄激素受体异常与雄激素不敏感综合征

雄激素受体异常与雄激素不敏感综合征田秦杰，黄尚志，葛秦生雄激素不敏感综合征（ａｎｄｒｏｇｅｎｉｎｓｅｎｓｉｔｉｖｉｔｙｓｙｎｄｒｏｍｅ，ＡＩＳ）是一种单基因突变所致的性发育表型异常，其核型为４６，ＸＹ，性腺为睾丸，睾酮分泌正常，由于雄激素的正常效应全...     

维吾尔族前列腺癌与雄激素受体CAG重复多态性的关系

目的　探讨雄激素受体 (androgenreceptor ,AR )基因CAG重复长度与维吾尔族前列腺癌(prostatecancer ,PC)危险性及临床表现的关系。方法　应用PCR和直接测序的方法对维吾尔族 3 1例PC和 80名健康老年男性患者外周血标本进行AR基因CAG重复长度测定。结果　PC和对照组AR基因CAG重复长度平均为 2 2 .3和 2 2 .8,范围为 13 3 0 ,两者比较差异无显著性 (P =0 .5 72 )。AR基因CAG重复长度 <2 2与≥ 2 2比较 ,OR值为 2 .3 2 ( 95 %可信区间为 1.0 0 5 .46,P =0 .0 5 ) ,AR基因CAG重复长度与PC发病年龄 (相关系数 0 .2 0 1,P =0 .2 8)、前列腺特异抗原 (相关系数 -0 .0 92 ,P =0 .62 )无相关性 ,与前列腺癌分级也无关 (P >0 .0 5 )。结论　短的AR基因CAG重复长度与维吾尔族前列腺癌的危险性有关 ,而与前列腺癌的发病年龄、PSA水平及病理分级无关。     

雄激素受体和卵泡刺激素受体在成年大鼠睾丸中期的依赖性表达

目的 确定雄激素受体（AR）和卵泡刺激素受体（FSHR）在大鼠睾丸中的细胞定位和表达变化。方法 利用地高辛标记的cRNA探针,在成年大鼠睾丸冰冻切片上进行原位杂交;同时利用透光显微切割技术将成年大鼠曲细精管分为Ⅱ-Ⅵ、Ⅶ-Ⅷ、Ⅸ-Ⅻ、XIII－Ⅰ4个阶段,撮总RNA,用α－^32P标记的cDNA探外进行斑点杂交,观察AR和FSHR mRNA表达的细胞定位和期依赖性变化。利用图像分析系统,对阳性杂交信号单位面积平均辉度进行定量分析。结果 AR mRNA阳性杂交信号位于支持细胞和间质细胞,于Ⅶ-Ⅷ期最强,Ⅸ-Ⅰ期最弱;FSHR mRNA阳性杂交信号位于支持细胞,于XIII－Ⅰ期最强,Ⅶ-Ⅷ期最弱。各阶段之间具有非常显著性差异（P＜0.01）。结论 AR和FSHR期依赖性表达的不同规律提示T（睾酮）和FSH（卵泡刺激素）作用于精子发生的不同阶段,说明睾酮和卵泡刺激素协同作用调节成年大鼠的精子发生。这一结论将为人类生育调控和不孕症的治疗提供新思路。     

雄激素受体和卵泡刺激素受体在成年大鼠睾丸中的期依赖性表达

目的　确定雄激素受体 (AR)和卵泡刺激素受体 (FSHR)在大鼠睾丸中的细胞定位和表达变化。　方法　利用地高辛标记的cRNA探针 ,在成年大鼠睾丸冰冻切片上进行原位杂交 ;同时利用透光显微切割技术将成年大鼠曲细精管分为Ⅱ～Ⅵ、Ⅶ～Ⅷ、Ⅸ～Ⅻ、ⅩⅢ～Ⅰ 4个阶段 ,提取总RNA ,用α 32 P标记的cDNA探针进行斑点杂交 ,观察AR和FSHRmRNA表达的细胞定位和期依赖性变化。利用图像分析系统 ,对阳性杂交信号单位面积平均辉度进行定量分析。　结果　ARmRNA阳性杂交信号位于支持细胞和间质细胞 ,于Ⅶ～Ⅷ期最强 ,Ⅸ～Ⅰ期最弱 ;FSHRmRNA阳性杂交信号位于支持细胞 ,于ⅩⅢ～Ⅰ期最强 ,Ⅶ～Ⅷ期最弱。各阶段之间具有非常显著性差异 (P<0 0 1)。　结论　AR和FSHR期依赖性表达的不同规律提示T(睾酮 )和FSH(卵泡刺激素 )作用于精子发生的不同阶段 ,说明睾酮和卵泡刺激素协同作用调节成年大鼠的精子发生。这一结论将为人类生育调控和不孕症的治疗提供新思路     

前列腺癌中发现的4种雄激素受体突变体在PC3细胞中转录激活功能的研究

目的 :雄激素受体 (AR)基因突变在前列腺癌 (PC)的发生、发展中具有重要作用。本实验室曾应用PCR -SSCP法 ,从 5 0余例PC患者肿瘤组织中筛选出 4种AR基因点突变 (G14 2V、D2 2 1H、E872Q、M886I) ,它们均位于AR重要的功能区中。本实验拟观察在雄激素的激动剂二氢睾酮 (DHT)以及其他甾体激素 (雌二醇及孕激素 )作用下 ,这 4种突变体在前列腺癌细胞系PC3中转录激活功能的变化 ,为阐明AR基因突变对AR功能的影响及其在前列腺癌发生、发展和治疗中的作用提供理论依据。方法 :将野生型AR(wtAR)或AR突变体的表达载体与报告基因 (p…     

雄激素受体蛋白表达及其基因获得/缺失与前列腺癌预后的相关性

目的 探讨雄激素受体（AR）蛋白表达及其基因获得/缺失改变与前列腺癌患者预后的关系。方法 前列腺癌患者19例,年龄58～90岁,平均72岁,治疗前PSA为(13.3～120)ng/mL,Gleason分级,其中高分化（Gleason评分﹤7分）2例,低分化（Gleason评分≥7分）17例。用免疫组化和FISH检测19例前列腺癌患者前列腺癌组织中的AR蛋白表达及其基因获得/缺失改变。结合临床资料分析其与前列腺癌预后的相关性。结果 19例中,发生AR基因获得2例,未发生AR基因获得17例,获得率为10.5%。其中2 例发生AR基因获得标本均来自存活组,6例死亡组病例中,无一例发生AR基因获得。未复发组阳性强度显著高于死亡组（P <0.05）。结论 前列腺癌患者AR蛋白表达中强阳性以及在治疗前出现AR基因获得可能提示预后良好。     

雄激素及其受体与多囊卵巢综合征

多囊卵巢综合征(PCOS)是育龄期妇女常见的一种内分泌代谢性疾病,发病率为5%~10%,其发病机制尚未完全阐明。高雄激素血症是PCOS的突出特点,尤其是卵巢局部的高雄激素环境是导致PCOS的关键原因,因此对高雄激素形成这一特征性改变的研究成为阐明PCOS病因的重点所在。雄激素主要通过激活雄激素受体(AR)来发挥作用,故AR的作用不容忽视,我们着重就雄激素和AR在PCOS发病中的作用作一综述。     

无雄激素条件下表皮生长因子诱导前列腺癌细胞系增殖及雄激素受体磷酸化

目的探讨在无雄激素的条件下,表皮生长因子对前列腺癌细胞增殖及雄激素受体磷酸化的影响。方法以LNCaP及LAPC4 AR为研究对象,在无雄激素的条件下,EGF处理后,Western blot方法测定LNCaP及LAPC4 AR磷酸化状态;siRNA转染方法敲除Src基因或Ack1基因,观察对AR磷酸化的影响;CCK-8检测细胞增殖;定时定量RT-PCR检测前列腺特异抗原及人体激肽释放酶2 mRNA表达。结果 EGF通过Src激酶和另一未知激酶导致AR Tyr-534及AR Tyr-267特异位点磷酸化;相比未用EGF对照组,EGF能够促进前列腺癌细胞增殖(P0.05),增加前列腺特异抗原(P0.05)及人体激肽释放酶2 mRNA表达(P0.05)。结论 EGF通过细胞内非受体酪氨酸激酶使AR特异位点磷酸化,诱导前列腺癌细胞增殖。     

阿片类生长因子受体抑制雄激素依赖性前列腺癌LNCaP细胞的生长

目的:观察阿片类生长因子受体(opioid growth factor receptor,OGFr)对雄激素依赖性前列腺癌LNCaP细胞活力的影响.方法:将LNCaP细胞随机分为非转染组、空白质粒组(转染pcDNA3.1空白质粒)和OGFr质粒组(转染表达质粒pcDNA3.1-OGFr),RT-qPCR和Western...     

Making Sense of Intratumor Genetic Heterogeneity: Altered Frequency of Androgen Receptor CAG Repeat Length Variants in Breast Cancer Tissues

To examine the significance of intratumor genetic heterogeneity (ITGH) of the androgen receptor (AR) gene in breast cancer, patient‐matched samples of laser capture microdissected breast tumor cells, adjacent normal breast epithelia cells, and peripheral blood leukocytes were sequenced using a novel next generation sequencing protocol. This protocol measured the frequency of distribution of a variable AR CAG repeat length, a functional polymorphism associated with breast cancer risk. All samples exhibited some degree of ITGH with up to 30 CAG repeat length variants identified. Each type of tissue exhibited a different distribution profile of CAG repeat lengths with substantial differences in the frequencies of zero and 18–25 CAG AR variants. Tissue differences in the frequency of ARs with each of these CAG repeat lengths were significant as measured by paired, twin t‐tests. These results suggest that preferential selection of 18–25 CAG repeat length variants in breast tumors may be associated with breast cancer, and support the observation that shorter CAG repeats may protect against breast cancer. They also suggest that merely identifying variant genes will be insufficient to determine the critical mutational events of oncogenesis, which will require measuring the frequency of distribution of mutations within cancerous and matching normal tissues.     

Stromal Androgen Receptor in Prostate Development and Cancer

The androgen receptor (AR) in stromal cells contributes significantly to the development and growth of prostate during fetal stages as well as during prostate carcinogenesis and cancer progression. During prostate development, stromal AR induces and promotes epithelial cell growth, as observed from tissue recombinant and mouse knockout studies. During prostate carcinogenesis and progression, the stromal cells begin to lose AR expression as early as at the stage of high-grade prostatic intraepithelial neoplasia. The extent of loss of stromal AR is directly proportional to the degree of differentiation (Gleason grade) and progression of prostate cancer (PCa). Co-culture studies suggested that stromal AR inhibits the growth of malignant epithelial cells, possibly through expression of certain paracrine factors in the presence of androgens. This functional reversal of stromal AR, from growth promotion during fetal prostate development to mediating certain growth-inhibiting effects in cancer, explains to some extent the reason that loss of AR expression in stromal cells may be crucial for development of resistance to androgen ablation therapy for PCa. From a translational perspective, it generates the need to re-examine the current therapeutic options and opens a fundamental new direction for therapeutic interventions, especially in advanced PCa.CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.Prostate cancer (PCa) is the most common non-skin malignancy in the male population within the United States and is the second most common cancer in men worldwide.¹ It is also one of the leading causes of cancer-related deaths in males in the United States.Normal human prostate is composed of an epithelial tissue and an adjacent stroma. The epithelium is composed of two principal cell types, the tall columnar secretory luminal cells that line the glandular ducts and the flattened basal cells surrounding them. In addition, some rare neuroendocrine cells are also present. Often, the terms mesenchyme and stroma are loosely used. Herein, mesenchyme refers to the mesodermal-derived fetal or newborn tissues with instructive induction potential. The word stroma describes the tissues surrounding the prostatic epithelium, later in development. In the adult human prostate, the stroma is composed mainly of smooth muscle cells. However, it also includes some fibroblasts, nerves, blood vessels, and various infiltrating immune and inflammatory cell types.Circulating androgens mediate the development and function of prostate by stimulating the androgen receptor (AR). Rat studies have shown that in stroma, AR is expressed in mesenchymal cells of the urogenital sinus (UGS), especially those adjacent to the epithelium, concurrent with the formation of prostatic buds.^2,3 As the prostate develops and the mesenchymal cells differentiate to form smooth muscle, AR expression is widespread, but not universal, throughout the muscle. In the past, investigators have mainly focused on studying epithelial AR function in prostate. Relatively limited data are available to describe the expression and function of stromal AR in prostate development^2–14 and cancer. Stromal AR is involved in both prostate development and prostate carcinogenesis, with distinct functions in these two processes. We examine the current knowledge and understanding of stromal AR function, including its translational significance.     

A New Missense Substitution at a Mutational Hot Spot of the Androgen Receptor in SiblingsWith Complete Androgen Insensitivity Syndrome

Several mutations have been described in the human androgen receptor gene including constitutional mutations in androgen insensitivity syndrome, somatic mutations in prostate cancer and triplet expansions in Kennedy's disease (Gottlieb et al. 1997). Here we report on two siblings with complete androgen insensitivity and a novel missense mutation, D695V, in their androgen receptor gene. The two XY females are siblings of German descent and presented at the ages of 23 and 19 years, respectively, with typical clinical features of complete androgen insensitivity. We found both siblings to be hemizygous for a new adenine to thymine transversion at the second nucleotide of codon 695 within the fourth exon of the human androgen receptor gene. The resulting missense mutation D695V is located at the amino-terminal border of the ligand- binding domain of the androgen receptor. The aspartic acid residue at this position is highly conserved in the steroid binding domains of other members of the nuclear receptor family and has already been found to be the site of two other missense mutations associated with androgen insensitivity syndrome (Ris Stalpers et al. 1991, Hiort et al. 1996). Three of four reported subjects showed the complete androgen insensitivity phenotype, in accordance with the two siblings in our study. We suggest that the existence of three pathological amino acid substitutions for aspartic acid 695 most likely reflects the essential role of this residue for normal androgen receptor function in male sexual differentiation.     

Immunolocalization of Androgen Receptor and Estrogen Receptors in Skin Tags

Abstract

Skin tags (STs) are benign connective tissue tumors of the dermis. Several clinical observations suggested the involvement of sex steroids in their development. This study aimed at investigating the possible role of androgen receptor (AR) and estrogen receptors (ERs) in STs pathogenesis through their immunohistochemical (IHC) localization in skin biopsies of this disease and to correlate their expression with different clinical and histopathological parameters. Using IHC techniques, we examined 62 cases with STs and 30 gender- and age-matched, healthy subjects, representing the control group. ERα, ERβ, and AR were upregulated in STs compared to normal skin in epidermis and dermis (p?<?.001 for all). Higher AR H score was significantly associated with axillary STs (p?=?.02), skin colored tags (p?=?.03), acanthosis, and papillomatosis (p?=?.04 for both). Higher ERα H score was significantly associated with hyperpigmented tags (p?<?.001) and positive family history (p?=?.003). Higher ERβ H score was significantly associated with female gender and obesity (p?=?.004 for both). Higher ERα and AR H scores were significantly associated with loose collagen arrangement (p?=?.02, p?=?.004, respectively). Higher AR, ERα, and ERβ H scores were significantly associated with the presence of mast cells (p?=?.01, p?=?.04, p?=?.002, respectively) and dilated blood vessels (p?=?.006, p?=?.04, p?=?.04, respectively). In conclusion, AR and ERs may share in STs pathogenesis through their effect on keratinocytes, fibroblasts, and mast cells.     

Immunoexpression of Androgen Receptor in the Nontumorous Pituitary and in Adenomas

Little information is available regarding androgen receptor immunoexpression (AR) in the normal and neoplastic human pituitary. Available experimental data links it to primarily gonadotroph cells. We undertook an immunohistochemical study of 41 autopsy-derived normal glands from patients of both sexes and all ages as well as 79 fully characterized pituitary adenomas of all types, the focus being upon AR expression in normal and neoplastic gonadotrophs. Nuclear AR immunoreactivity was noted in gonadotrophs and other normal adeno- and neurohypophysial cells. In addition to its presence in 74% of gonadotroph and 55% of null cell adenomas, lesser proportions of other adenoma types (adrenocorticotropic hormone 50%, prolactin 38%, growth hormone 33%) also exhibited AR immunoreactivity. No staining of thyroid-stimulating hormone adenomas was noted. The physiologic significance of our findings remains to be explored. The literature regarding AR expression in animal and human pituitaries is reviewed.     

The Expression of the Androgen Receptor and Estrogen Receptor 1 is Related to Sex Dimorphism in the Gerbil Prostate Development

The development of the prostate gland in females has not yet been clearly elucidated, and the sexual dimorphism associated with such gland development in general is far from being understood. In the present study, we used tridimensional (3D) reconstructions and histochemical and immunohistochemical techniques to describe the sexual dimorphism and its causes in the early postnatal development of the prostate in male and female Mongolian gerbils (Meriones unguiculatus). We observed that the female prostate was smaller, had fewer branches throughout the development, and underwent differentiation earlier than that in males. Also, the expression of the estrogen receptor 1 (ESR1 or ER‐alpha) and fibroblast growth factor 10 (FGF10) was decreased in the periductal region, and the expression of the androgen receptor (AR) was increased in the epithelium. All together, these changes decreased proliferation and branching and led to an earlier prematuration of the female prostate. These new data shed light on the underlying mechanisms involved with the sexual dimorphism in the development of the prostate. Anat Rec, 299:1130–1139, 2016. © 2016 Wiley Periodicals, Inc.     

Stromal Androgen Receptor Roles in the Development of Normal Prostate,Benign Prostate Hyperplasia,and Prostate Cancer

The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa.The prostate contains mainly the stromal cells and epithelial cells that are separated by base members and merged in extracellular matrix. Stromal cells include fibroblasts, smooth muscle cells (SMCs), and other minor inflammatory cells, nerve cells, and endothelial cells.The prostate is developed from the endodermal urogenital sinus¹ that contains an outer layer of embryonic connective tissue urogenital sinus mesenchyme (UGM) and an inner layer of urogenital sinus epithelium (UGE).¹ The initial step of prostate development in UGM involves the differentiation of fibroblasts and SMCs,¹ and in response to the UGM androgen/androgen receptor (AR) signals, UGE can grow into the surrounding stromal cells and develop into the prostate epithelial cells as part of the normal prostate development.The ability of the UGM to induce epithelial development and the developed epithelial cells, in return, to direct UGM to undergo differentiation, suggesting that the reciprocal developmental interactions between UGM and UGE might be governed by androgen/AR signals, which are essential for the development of normal prostate, benign prostate hyperplasia (BPH), and prostate cancer (PCa). Prostate development factors, including its proliferation, differentiation, morphogenesis, and functional maintenance, are all influenced by androgen/AR signals.² Androgen/AR signals also play vital roles in the initiation and progression of BPH and PCa,^3,4 which may require the proper interaction with various AR coregulators.²AR is a member of the nuclear receptor superfamily that can be activated and translocated from cytoplasm to nucleus after binding the testosterone or dihydrotestosterone.^5–7 In prostate, AR is expressed in both epithelial and stromal tissues. The transactivated AR in nucleus may then function through modulation of various downstream target genes to influence the development and maintenance of the prostate. In addition to influencing cell growth directly, epithelial AR and stromal AR can also function through epithelial-mesenchymal transition (EMT) to influence prostate development. EMT is a process by which epithelial cells lose their cell-cell adhesion and gain migratory properties to become mesenchymal-like and/or mesenchymal stem cells. These potent mesenchymal cells may then differentiate into different cell types to influence the progression of BHP⁸ and PCa.⁹This review will focus on the discussion of the roles of stromal AR in the development of normal prostate and prostate diseases.     

Effectiveness of Adding Docetaxel to Androgen Deprivation Therapy for Metastatic Hormone-Sensitive Prostate Cancer in Korean Real-World Practice

PurposeEvidence in favor of adding docetaxel in treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has led to docetaxel in conjunction with androgen deprivation therapy (ADT) as standard therapy. The aim of this study was to examine the effectiveness of docetaxel with ADT for Korean patients with mHSPC in real-world practice.Materials and MethodsA retrospective cohort study was performed at six Korean hospitals for patients with mHSPC treated with docetaxel plus ADT. Patients were treated every 3 weeks for up to six cycles with 75 mg/m² of docetaxel. The primary endpoint was time to castration resistant prostate cancer (CRPC).ResultsThis study included 46 eligible patients from June 2016 to February 2021. Median age was 68.5 years (range, 52–84) and all patients present with de novo M1 with high-volume disease. The median prostate-specific antigen (PSA) level at ADT initiation was 205.4 (7.7–1933) ng/mL, and time from ADT to docetaxel was 2.4 months (0–5.3). All six planned cycles of docetaxel were delivered in 36 patients (78%), 7 patients (15%) discontinued treatment due to adverse events, and 3 patients (7%) discontinued due to progression. At the time of the analysis, CRPC had developed in 34 patients (74%), and the median time to CRPC was 18.0 (95% confidence interval, 14.1–21.9) months. PSA <0.2 ng/mL was achieved in 11 patients (24%) after 6 months of ADT and in 10 patients (22%) after 12 months. At last follow-up, 35 patients (76%) were alive; the median overall survival was not reached.ConclusionThe effect of docetaxel combined with ADT for Korean patients with mHSPC is comparable with prior results in Western studies.