Androgen and Wnt signaling in bladder cancer

摘要 膀胱癌在男性中排名第四，在女性中排名第11。尽管有这样的膀胱 发育和功能不依赖性激素，男性发育的可能性是男性的三倍 膀胱癌的发病率高于女性。吸烟已被证明不是造成这种性别偏见的原因。相反， 固有的性别差异可能是男性对膀胱癌易感性的分子机制。 性激素和性染色体显然是造成这种男性嗜好的原因 膀胱癌。事实上，在啮齿动物身上的实验证据有力地支持了雄激素的关键作用。 受体在化学诱导的膀胱癌模型中促进肿瘤发展的作用。除了……之外 雄激素信号，另一个不可否认的强大的下尿路发育调节因子和 致癌是WNT信号转导途径。β-catenin是规范的wnt信号的信号整合者 AR和β-连环蛋白在物理上相互作用，协同激活转录。这种互动是至关重要的 在生殖器男性化、膀胱癌发生和 进步。尽管这两个通路在膀胱癌的发生中起着关键作用，但它们直接 转录靶点，可能是膀胱癌发生的驱动因素，仍然难以捉摸。在这 应用，我们建议使用最近发展起来的一种强大的技术，Split DamID来揭示活体 膀胱癌发生过程中AR、p300和β-catenin下游转录靶点的研究在AIM 1，我们将使用我们新产生的转基因模型来揭示AR和p300的直接转录靶点 致癌物诱导的膀胱癌模型。接下来，在目标2中，我们将在膀胱器官上使用SpDamID来 揭示AR和β-catenin的直接靶点，然后对它们的促进作用进行siRNA功能筛选 有机体的形成。总之，这些研究应该会极大地提高我们对膀胱癌的理解。 启动，尤其是由AR和Wnt信号控制的那些。

ABSTRACT Bladder cancer is the 4th most common cancer in men and 11th in women. Despite that bladder development and function are not sex hormone-dependent, men are three times more likely to develop bladder cancer than women. Smoking has been shown not to be a contributor for this gender bias. Instead, intrinsic sex-differences likely underpin the molecular mechanism for male susceptibility to bladder cancer. Sex hormones and sex chromosomes are obvious suspects to account for this male predilection for bladder cancer. In fact, experimental evidence in rodents strongly support a crucial role for androgen receptor in promoting cancer development in a chemical-induced bladder cancer model. In addition to androgen signaling, the other undeniably powerful regulator of lower urinary tract development and carcinogenesis is the WNT signaling pathway. β-catenin is the signal integrator of canonical WNT signaling and AR and β-catenin physically interact to synergistically activate transcription. This interaction is crucial for downstream target expression during genital masculinization, bladder cancer development and progression. Despite the crucial roles these two pathways play in bladder carcinogenesis, their direct transcriptional targets, which are likely drivers of bladder cancer initiation, remain elusive. In this application, we propose to use a recently developed powerful technology, Split DamID to reveal in vivo transcriptional targets downstream of AR, p300 and β-catenin during bladder cancer development. In Aim 1, we will use our newly generated transgenic model to reveal direct AR and p300 transcriptional targets in a carcinogen-induced bladder cancer model. Next, in Aim 2, we will use SpDamID on bladder organoids to reveal AR and β-catenin direct targets, followed by siRNA functional screen for their roles in promoting organoid formation. Together, these studies should greatly improve our understanding of bladder cancer initiation, especially those controlled by AR and Wnt signaling.