Decoding NanogP8 in Tumorigenesis

解码肿瘤发生中的 NanogP8

基本信息

批准号：
8470137
负责人：
Dean G Tang
金额：
$ 30.82万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470137
关键词：
Address Androgens Animal Model Benign Biological CD44 gene CDKN2A gene Castration Cells ChIP-seq Chromosomes, Human, Pair 12 Chromosomes, Human, Pair 15 Clinical Clinical Treatment Clonal Evolution Colon Carcinoma DNA Binding Data Development Distant Metastasis Embryo Embryonic Development Epithelial Cells Exhibits Gene Expression Gene Expression Profile Genome Goals Heterogeneity Homologous Gene Human Hyperplasia In Vitro Knowledge Lead Lesion Longevity Malignant Neoplasms Malignant neoplasm of prostate Mediating Molecular Molecular Mechanisms of Action Molecular Profiling Natural regeneration Nature Neurosecretory Systems Organ Play Population Property Prostate Proteins Publishing Recurrence Reporter Reporting Resistance Role Serum Signal Pathway Stem cells System Telomerase Testing Therapeutic Time Transgenic Animals Video Microscopy Work anti-cancer therapeutic base cancer cell cancer stem cell castration resistant prostate cancer clinically significant embryonic stem cell homeodomain in vivo knock-down malignant breast neoplasm neoplastic cell novel overexpression pluripotency progenitor promoter prostate cancer cell research study response screening self-renewal senescence small hairpin RNA stem stemness transcription factor tumor tumorigenesis tumorigenic

项目摘要

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.

描述（由申请人提供）：肿瘤发生类似于异常胚胎发生。与发育中的器官一样，肿瘤包含一系列表型异质细胞，并且可能含有通常称为癌症干细胞（CSC）的干细胞样细胞。尽管CSC的概念仍存在争议，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，恶性肿瘤在人群水平上具有永生性。治疗意义中尚未解答的关键生物学问题之一是一般癌细胞，特别是癌症干细胞如何在分子水平上对其自我永存（永生）致瘤潜力（即自我更新特性）进行调节。值得注意的是，恶性细胞与胚胎 SC (ESC) 具有相似的基因表达谱，胚胎 SC 表达几个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 号染色体上的同源域转录因子。 PCa 和其他癌细胞不表达 Nanog1，而是表达逆转录 Nanog1 同源物，称为 NanogP8，位于 15 号染色体上。敲除 NanogP8 会显着抑制CSC 的体外特性以及 PCa 和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，并显着促进去势抵抗性 PCa 或 CRPC 的发展。我们最近的全基因组 ChIP-Seq 实验发现了独特的 NanogP8 DNA 结合谱。此外，新产生的 NanogP8 转基因动物在靶器官中出现增生性病变。这些观察结果综合起来得出我们的总体假设：1) NanogP8 具有促肿瘤活性； 2）NanogP8通过独特的信号通路调节CSC自我更新，促进肿瘤发展； 3）NanogP8在CRPC的发展中起着因果作用。当前的项目主要在 PCa 中测试这些假设，具有以下三个具体目标。 1) 检验NanogP8与CRPC的发生有因果关系的假设； 2) 阐明NanogP8的细胞和分子作用机制； 3) 使用新型转基因动物模型探索 NanogP8 的促肿瘤作用。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 CSC 的永生性并有助于肿瘤发展和 CRPC 的理解。它还将促进专门针对 PCSC 的基于机制的疗法的开发。