Developmental Transcription Factors in Prostate Cancer

前列腺癌的发育转录因子

基本信息

批准号：
8214180
负责人：
CARLOS Sanchez MORENO
金额：
$ 8.42万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-10 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8214180
关键词：
Affect American Animal Model Animals Apoptosis Attenuated BMP7 gene Binding Biological Assay Biological Markers Cancer Cell Growth Cancer Patient Cell Cycle Arrest Cell Survival Cells Cessation of life Clinical Clinical Treatment Clinical Trials Code DNA Damage DNA Repair Gene Data Development Disease Doxycycline ES02 Epigenetic Process Feedback Gene Expression Gene Targeting Genes Genomic Instability Growth Factor Receptors HOXC6 gene Health Human In Vitro Knowledge Lead Ligands Light Link Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Metastatic to Methylation MicroRNAs Modeling Molecular Profiling Mus Neoplasm Metastasis Nuclear Oncogenic PTEN gene Pathway interactions Patients Peptide Hydrolases Phenotype Post-Translational Protein Processing Process Prostate Proteins Recurrence Regulation Regulator Genes Role Signal Transduction Stem cells Testing Therapeutic Intervention Tumor Suppressor Genes Undifferentiated Work Xenograft procedure cancer cell cancer type follow-up human disease in vivo inhibitor/antagonist insight men mouse model notch protein novel outcome forecast overexpression pre-clinical presenilin-1 research study response small hairpin RNA therapeutic target transcription factor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the most prevalent non-cutaneous malignancy in American men, with estimates for 2007 at over 218,000 new cases and 27,000 deaths. The developmental transcription factors SOX4 and HOXC6 are strongly correlated with prostate cancer progression. During the past three years, we have identified hundreds of direct targets of these transcription factors, elucidating the transcriptional networks that they regulate, and providing mechanisms for their action. Insights from our studies suggest that SOX4 and HOXC6 represent novel links between the Wnt and Notch pathways. Both the Wnt and Notch pathways are conserved developmental pathways that are often activated in human cancers and that represent new opportunities for therapeutic intervention. SOX4 is both a target and effector of the Wnt pathway and directly interacts with ?-catenin to activate gene expression. Our preliminary studies show that HOXC6 normally provides negative feedback to the Wnt pathway, but this feedback is lost during oncogenesis via epigenetic silencing of HOXC6 target genes. We have also discovered that SOX4 and HOXC6 regulate several Notch pathway components and Notch downstream targets. Thus, we hypothesize that overexpression of SOX4 and HOXC6 results in cooperative activation of the Wnt and Notch pathways during prostate cancer progression and metastasis, maintaining an undifferentiated, transit-amplifying, progenitor cell phenotype. SOX4 and HOXC6 also activate expression of several growth factor receptors that promote cancer cell growth and survival. Furthermore, we have new data suggesting that SOX4 and HOXC6 work in concert to alter miRNA and protein-coding gene expression to promote cell survival in the presence of genomic instability and DNA damage. In light of our continued progress and new exciting preliminary data, we plan to increase our understanding of how these key oncogenic transcription factors contribute to cancer progression and metastasis through three specific aims. We will test whether HOXC6 and SOX4 cooperate to activate Notch signaling in vitro and in animal models with prostate-specific, inducible expression of these genes. We will test whether SOX4 is a crucial link between the Wnt and Notch pathways, and whether HOXC6 can repress Wnt signaling upon treatment of cells with demethylating agents. Finally, we will test whether SOX4 and HOXC6 regulate predictive biomarker genes involved in cellular responses to genomic instability. These proposed studies will provide fundamental knowledge highly pertinent to many types of cancer, new mechanistic insights specifically into prostate cancer bone metastases, and preclinical data that could lead to new clinical trials for treatment of metastatic prostate cancer patients with poor prognoses. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most prevalent cancer in American men, with estimates for 2007 at over 218,000 new cases and 27,000 deaths, primarily due to metastatic disease. In this project, we plan to study the relationship of two critical regulatory genes with the pathways that they control and how this impacts cancer progression and metastasis. Experiments are directed to determine whether these genes, or the pathways that they influence, are viable therapeutic targets using a variety of approaches, including mouse models.

描述（由申请人提供）：前列腺癌是美国男性中最普遍的非乳头恶性肿瘤，2007年估计为218,000例新病例和27,000例死亡。 Sox4和Hoxc6的发育转录因子与前列腺癌的进展密切相关。在过去的三年中，我们确定了这些转录因子的数百个直接目标，阐明了它们调节的转录网络，并为其作用提供了机制。我们研究的见解表明，Sox4和Hoxc6代表了Wnt和Notch途径之间的新联系。 Wnt和Notch途径都是保守的发育途径，通常在人类癌症中被激活，代表了治疗干预的新机会。 Sox4既是Wnt途径的靶标和效应子，又直接与-Catenin相互作用以激活基因表达。我们的初步研究表明，HOXC6通常会对Wnt途径提供负反馈，但是这种反馈在肿瘤发生期间通过HOXC6靶基因的表观遗传沉默而丧失。我们还发现Sox4和Hoxc6调节了几个Notch途径组件和下游目标。因此，我们假设SOX4和HOXC6的过表达导致前列腺癌进展和转移期间Wnt和Notch途径的合作激活，从而保持了未分化的，不明转移的祖细胞细胞表型。 SOX4和HOXC6还激活了促进癌细胞生长和存活的几种生长因子受体的表达。此外，我们有新的数据表明，Sox4和Hoxc6协同起作用，可以改变miRNA和蛋白质编码基因表达，以在存在基因组不稳定性和DNA损伤的情况下促进细胞存活。鉴于我们持续的进步和新的令人兴奋的初步数据，我们计划通过三个特定目标来提高对这些关键的致癌转录因子如何有助于癌症进展和转移的理解。我们将测试HOXC6和SOX4是否合作以在体外和具有前列腺特异性，可诱导表达的动物模型中激活Notch信号传导。我们将测试SOX4是否是Wnt和Notch途径之间的关键联系，以及HOXC6是否可以在用脱甲基剂处理细胞后抑制Wnt信号传导。最后，我们将测试SOX4和HOXC6是否调节与基因组不稳定性的细胞反应有关的预测生物标志物基因。这些提出的研究将提供与许多类型的癌症，专门针对前列腺癌骨转移酶的新机械见解高度相关的基本知识，以及可能导致新的临床试验来治疗前列腺前列腺癌患者的新临床试验。公共卫生相关性：前列腺癌是美国男性中最普遍的癌症，估计2007年的218,000例新病例和27,000例死亡，主要是由于转移性疾病。在这个项目中，我们计划研究两个关键调节基因与它们控制的途径以及这如何影响癌症进展和转移的关系。实验是指确定这些基因或它们影响的途径是使用多种方法（包括小鼠模型）的可行治疗靶标。