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: 8115717
• 负责人: CHAWNSHANG CHANG
• 金额: $ 32.06万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115717
• 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. PUBLIC HEALTH RELEVANCE: Urinary bladder cancer 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 reasons behind this sex difference in incidence are unknown. Recent studies have suggested the involvement of androgens/androgen receptor (AR) signaling in bladder cancer progression. Using AR knockout (ARKO) mice, we found that the male hormone androgen/AR signaling might play a critical role in the development of the chemical carcinogen, BBN, induced bladder carcinogenesis. We also found near 25% of ARKO mice develop bladder tumors after treatment with BBN and the androgen, dihydrotestosterone (DHT), suggesting DHT is able to function through non-AR pathways to promote bladder tumor progression. We will use this proposal to prove our hypothesis that DHT can function through non-AR pathways to promote bladder cancer progression.

描述（由申请人提供）：膀胱癌（BCa）是美国男性/女性中第四/第十常见的癌症。据报告，男性患膀胱癌的风险明显高于女性（约三倍）。然而，发病率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）信号转导参与BCa进展。利用AR基因敲除（ARKO）小鼠，我们发现雄激素/AR信号在化学致癌物N-丁基-N-4-羟基丁基-亚硝胺（BBN）诱导的膀胱癌发生中可能起关键作用。在BBN治疗下，缺乏AR且具有不可检测的雄激素的ARKO小鼠没有发生膀胱肿瘤，而它们的野生型同窝出生的具有功能性AR的小鼠在50周龄时都发生膀胱肿瘤。有趣且出乎意料的是，我们发现在补充雄激素双氢睾酮（DHT）后，近25%的ARKO小鼠发生BBN诱导的膀胱肿瘤，提示DHT能够通过非AR途径发挥作用以促进膀胱肿瘤进展。这一发现在人AR阴性膀胱癌细胞系TCC 5637中得到进一步证实，表明添加DHT可以促进这种AR阴性膀胱细胞的生长和侵袭。初步数据还显示，在BCa AR阴性细胞中，DHT可增强G蛋白信号到ERK/MAPK-MEK信号的通路。基于这些体外人类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的机制。目的1：利用Uro-SV 40 T-ARKO小鼠模型证明DHT通过非AR途径促进BCa的进展。目的2：利用UPII-Ha-ras-ARKO小鼠模型证明DHT通过非AR途径促进BCa的进展。目标三：使用细胞转化/肿瘤发生试验来证明DHT可以通过非AR介导的途径来促进BCa起始和/或进展。目标4：利用人AR阴性膀胱癌细胞系证明DHT可以通过非AR途径促进BCa生长和侵袭，并剖析其潜在机制。影响：目前，人类中的BCa通常不被认为是睾丸依赖性的，因此不认为雄激素剥夺治疗（ADT）联合化学或手术去势是BCa患者抑制肿瘤进展的有效治疗选择。该提案的成功证明了DHT可以通过非AR途径发挥作用以促进膀胱癌的发生和进展，不仅为新的雄激素机制提供了体内证据，还可以回答先前使用ADT抑制雄激素与AR结合以治疗BCa患者失败的难题，并可能提供抑制BCa的新的预防/治疗方法。 公共卫生相关性： 膀胱癌是美国男性/女性中第四/第十位最常见的癌症。据报告，男性患膀胱癌的风险明显高于女性（约三倍）。然而，发病率性别差异背后的原因尚不清楚。最近的研究表明，雄激素/雄激素受体（AR）信号转导参与膀胱癌的进展。使用AR敲除（ARKO）小鼠，我们发现雄性激素雄激素/AR信号可能在化学致癌物BBN诱导的膀胱癌发生中起关键作用。我们还发现，近25%的ARKO小鼠在用BBN和雄激素双氢睾酮（DHT）治疗后发生膀胱肿瘤，这表明DHT能够通过非AR途径发挥作用，促进膀胱肿瘤进展。我们将用这个建议来证明我们的假设，即DHT可以通过非AR途径促进膀胱癌的进展。