Decoding NanogP8 in Tumorigenesis

描述（由申请人提供）：肿瘤发生类似于异常胚胎发生。像发育中的器官一样，肿瘤由一系列表型异质性细胞组成，可能含有通常被称为癌症干细胞（CSCs）的干细胞样细胞。尽管CSC的概念仍有争议，CSC的真正分子性质和临床意义仍有待充分阐明，但不可否认的是，恶性肿瘤在群体水平上是不朽的。一个关键的未解决的治疗意义的生物学问题是，一般癌细胞，特别是csc如何在分子水平上调节其自我延续（不朽）致瘤潜能，即自我更新特性。值得注意的是，恶性细胞与胚胎SC （ESCs）具有相似的基因表达谱，胚胎SC表达几种自我更新和多能性的核心调节因子，包括Nanog（也称为Nanog1），这是一种位于12号染色体上的同源结构域转录因子。我们已经观察到，人类PCa和其他癌细胞不表达Nanog1，而是表达位于第15号染色体上的反转录的Nanog1同源物，称为NanogP8。敲除NanogP8可显著抑制体外培养的CSC特性和前列腺癌、乳腺癌和结肠癌细胞的肿瘤再生。相比之下，NanogP8过表达足以赋予CSC特性，增强肿瘤再生，并显著促进去势抵抗性PCa或CRPC的发展。我们最近的全基因组ChIP-Seq实验发现了不同的NanogP8 dna结合谱。此外，新生成的NanogP8转基因动物在靶器官中发生增生性病变。这些观察结果结合在一起，导致我们的总体假设：1)NanogP8具有致瘤活性；2) NanogP8通过独特的信号通路调控CSC自我更新，促进肿瘤发展；3)纳米p8在CRPC的形成中起因果作用。本项目主要在PCa中对这些假设进行检验，具体目的有以下三个：1)检验NanogP8与CRPC的发展有因果关系的假设；2)阐明NanogP8的细胞和分子作用机制；3)利用新型转基因动物模型探讨NanogP8的致瘤作用。影响：本文提出的目标的实现将极大地促进我们对NanogP8如何调节CSCs的不朽和促进肿瘤发展和CRPC的理解。它还将促进特异性靶向PCSCs的基于机制的治疗方法的发展。

DESCRIPTION (provided by applicant): Tumorigenesis resembles abnormal embryogenesis. Like developing organs, tumors comprise a spectrum of phenotypically heterogeneous cells and may harbor stem cell-like cells commonly referred to as cancer stem cells (CSCs). Although the CSC concept is still debated and the true molecular nature and clinical significance of CSCs remain to be fully elucidated, it is undeniable that malignant tumors are immortal at the population level. One of the key unanswered biological questions of therapeutic implication is how cancer cells in general and CSCs in particular are regulated at the molecular level with respect to their self-perpetuating (immortal) tumorigenic potential, i.e., self-renewal properties. Remarkably, malignant cells share a similar gene expression profile with embryonic SC (ESCs), which express several core regulators of self-renewal and pluripotency including Nanog (also called Nanog1), a homeodomain transcription factor located on chromosome 12. We have observed that human PCa and other cancer cells do NOT express Nanog1 but rather express a retrotransposed Nanog1 homolog, called NanogP8, located on chromosome 15. Knocking down NanogP8 significantly inhibits the CSC properties in vitro and tumor regeneration of PCa and breast and colon cancer cells. In contrast, NanogP8 overexpression is sufficient to confer CSC properties, enhances tumor regeneration, and, significantly, promotes development of castration-resistant PCa or CRPC. Our recent whole-genome ChIP-Seq experiment has uncovered distinct NanogP8 DNA-binding profiles. Furthermore, newly generated NanogP8 transgenic animals develop hyperplastic lesions in the target organs. These observations, taken together, lead to our overarching hypotheses that 1) NanogP8 possesses protumorigenic activity; 2) NanogP8 promotes tumor development by regulating CSC self-renewal via unique signaling pathways; and 3) NanogP8 plays a causal role in the development of CRPC. The current project tests these hypotheses, mainly, in PCa with the following three Specific Aims. 1) To test the hypothesis that NanogP8 is causally involved in the development of CRPC; 2) To elucidate the cellular and molecular mechanisms of action of NanogP8; and 3) To explore the protumorigenic roles of NanogP8 using novel transgenic animal models. Impact: Accomplishment of the goals proposed herein should greatly advance our understanding of how NanogP8 regulates the immortality of CSCs and contribute to tumor development and CRPC. It will also facilitate development of mechanism-based therapeutics that specifically targets PCSCs.