Non-AR mediated DHT-promoted Bladder Cancer initiation and progression

非 AR 介导的 DHT 促进膀胱癌的发生和进展

• 批准号: 8693963
• 负责人: CHAWNSHANG CHANG
• 金额: $ 31.1万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693963
• 关键词: AR gene; Aftercare; Age; Androgen Receptor; Androgens; Antiandrogen Therapy; Binding; Biological Assay; Bladder; Bladder Neoplasm; Cancer Patient; Cancer cell line; Castration; Cell Line; Cells; Chemicals; Data; Development; Etiology; Failure; Female; G-Protein Signaling Pathway; GTP-Binding Proteins; Growth; Hormones; Human; Human Cell Line; In Vitro; Incidence; Knockout Mice; MAP Kinase Gene; MEKs; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Mus; Nitrosamines; Pathway interactions; Play; Preventive; Receptor Signaling; Reporting; Role; Sex Characteristics; Signal Transduction; Stanolone; Supplementation; Therapeutic; Time; United States; Woman; base; cancer cell; cancer initiation; carcinogenesis; cell growth; cell transformation; chemical carcinogen; deprivation; effective therapy; high risk; in vivo; male; men; mouse model; novel; success; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Urinary bladder cancer (BCa) is the fourth/tenth most common cancer among men/women in the United States. It is reported that males have significantly (approximately three times) higher risk of bladder cancer than females. However, the etiology of this sex difference in incidence is unknown. Recent studies have suggested the involvement of androgens/androgen receptor (AR) signaling in BCa progression. Using AR knockout (ARKO) mice, we found that the androgen/AR signaling might play a critical role in the development of the chemical carcinogen, N-butyl-N-4-hydroxybutyl-nitrosamine (BBN), induced bladder carcinogenesis. With BBN treatment, ARKO mice, that lack AR and with undetectable androgen, did not develop bladder tumors while their wild type littermates, with functional AR, all develop bladder tumors at the age of 50 wks. Interestingly and unexpectedly, we found near 25% of ARKO mice develop BBN-induced bladder tumor after supplementation with the androgen, dihydrotestosterone (DHT), suggesting DHT is able to function through non-AR pathways to promote bladder tumor progression. This finding was further confirmed in the human AR-negative bladder cancer cell line, TCC5637, showing that addition of DHT can promote this AR-negative bladder cell growth and invasion. Preliminary data also showed DHT could enhance the pathways from G-proteins signals to ERK/MAPK-MEK signals in BCa AR- negative cells. Based on these in vitro human cell line and in vivo mice evidences, we hypothesize that DHT can function through non-AR pathways to promote BCa initiation, growth, and invasion. We will apply the following 4 aims to prove our hypothesis and dissect potential mechanisms. Aim 1: Using the Uro- SV40T-ARKO mouse model to prove DHT can go through non-AR pathways to promote BCa progression. Aim 2: Using UPII-Ha-ras-ARKO mouse model to prove DHT can go through non-AR pathways to promote BCa progression. Aim 3: Using cell transformation/tumorigenesis assays to prove DHT can go through non-AR mediated pathways to promote BCa initiation and/or progression. Aim 4: Using human AR-negative bladder cell lines to prove DHT can go through non-AR pathways to promote BCa growth and invasion and to dissect potential mechanisms. IMPACT: Currently, BCa in humans is not generally considered hormonally dependent and therefore it is not assumed that androgen deprivation therapy (ADT) with chemical or surgical castration can be an effective treatment option for BCa patients in order to repress tumor progression. The success of this proposal to prove DHT can function through non-AR pathways to promote bladder cancer initiation and progression, not only provides in vivo evidence for a novel androgen mechanism, it may also answer the puzzle for the previous failure of using ADT to suppress androgen binding to AR for the treatment of BCa patients and may provide a new preventive/therapeutic approach to suppress BCa.

描述（由申请人提供）：泌尿膀胱癌（BCA）是美国男性/女性中第四/第十大癌症。据报道，男性的膀胱癌风险明显高于女性。但是，这种性别差异的病因尚不清楚。最近的研究表明，雄激素/雄激素受体（AR）信号在BCA进展中受到参与。使用AR基因敲除（ARKO）小鼠，我们发现雄激素/AR信号传导可能在化学致癌物N-Butyl-N-4-羟基丁基硝基胺（BBN）的发育中起关键作用，诱导了膀胱癌。通过BBN治疗，缺乏AR且无法检测到的雄激素的Arko小鼠并未患有膀胱肿瘤，而其野生型同窝仔具有功能性AR，所有的都在50周龄时会出现膀胱肿瘤。有趣而出乎意料的是，我们发现，在补充雄激素，二氢睾丸激素（DHT）后，接近25％的Arko小鼠会出现BBN诱导的膀胱肿瘤，这表明DHT能够通过非AR途径来促进膀胱肿瘤进展。这一发现在人类阴性膀胱癌细胞系TCC5637中得到了进一步证实，表明DHT的添加可以促进这种Ar-Condergative膀胱细胞的生长和侵袭。初步数据还表明，DHT可以增强从G蛋白信号到BCA AR-PANS-PARSAN-PARSING细胞中ERK/MAPK-MEK信号的途径。基于这些体外人细胞系和体内小鼠的证据，我们假设DHT可以通过非AR途径发挥作用，以促进BCA的启动，生长和侵袭。我们将应用以下4个目标来证明我们的假设并剖析潜在机制。 AIM 1：使用Uro-SV40T-ARKO小鼠模型证明DHT可以通过非AR途径来促进BCA进展。 AIM 2：使用UPII-HA-RAS-ARKO小鼠模型证明DHT可以通过非AR途径来促进BCA进展。 AIM 3：使用细胞转化/肿瘤发生分析来证明DHT可以通过非AR介导的途径来促进BCA的启动和/或进展。 AIM 4：使用人类的膀胱膀胱细胞系证明DHT可以通过非AR途径来促进BCA的生长和侵袭并剖析潜在的机制。影响：目前，人类中的BCA通常不被认为是荷尔蒙依赖性的，因此不认为具有化学或手术cast割的雄激素剥夺治疗（ADT）对于BCA患者而言是一种有效的治疗选择，以抑制肿瘤的进展。这项证明DHT的提议的成功可以通过非AR途径来促进膀胱癌的启动和进展，不仅为新型雄激素机制提供了体内证据，而且还可以回答先前使用ADT抑制AR抑制AR与AR治疗的雄激素治疗的难题，并可能提供了治疗BCA患者的治疗方法，并提供了一种新的预防/治疗方法来抑制BCA。