Role of the tumor suppressor KLF6 in prostate cancer

肿瘤抑制因子 KLF6 在前列腺癌中的作用

基本信息

批准号：
8051725
负责人：
JOHN A MARTIGNETTI
金额：
$ 31.23万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-08 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8051725
关键词：
Accounting Affect Affinity Chromatography Alternative Splicing Behavior Binding Cancer Etiology Cell Proliferation Cessation of life Clinical Complement Coupled Cytoplasmic Protein Development Diagnosis Diagnostic Disease Engineering Event Family Family history of Gene Expression Gene Silencing Genes Genetic Goals Growth Histology Human Human Cell Line Image Investigation Link Luciferases Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Mediating Modeling Molecular Mus N-terminal Neoplasm Metastasis Nuclear Proteins Outcome PC3 cell line Pathway interactions Play Predisposition Prevalence Prostate Prostatic Neoplasms Protein Isoforms Proteins Proteomics RNA Splicing Recurrence Registries Research Personnel Resistance Resources Role Signal Transduction Pathway Small Interfering RNA Therapeutic Tissues Tumor Biology Tumor Suppressor Proteins Xenograft procedure Zinc Fingers cancer cell cancer risk cell behavior clinically relevant improved in vivo in vivo Model lifetime risk member men mouse model neoplastic cell programs protein complex protein protein interaction retroviral-mediated time use transcription factor tumor tumor growth tumor initiation tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is a leading cause of cancer death in men and diagnosed cases steadily increase. In the U.S., approximately 198,000 men will be diagnosed and 32,000 will die this year. Therefore, identification of causative genes and molecular pathways underlying prostate tumor initiation, growth and metastatic spread represents an urgent priority for the rationale development of improved diagnostics and preventative and therapeutic strategies. We demonstrated that the tumor suppressor KLF6, a member of the Kruppel-like family of zinc finger transcription factors which regulate growth-related signal transduction pathways, is frequently inactivated in human PCa. Two lines of evidence now suggest that KLF6 status can both define PCa susceptibility and long-term outcome. First, in a multi-institutional study of over 3,400 men, we have shown that a specific germline KLF6 SNP, regardless of family history of disease, increases lifetime risk of PCa. This SNP increases KLF6 gene alternative splicing to yield a biologically active, growth- promoting isoform, KLF6-SV1, that increases tumor cell proliferation, invasion, and in vivo tumor growth. Second, multiple gene expression studies link decreased KLF6 expression with tumor recurrence, poor clinical outcomes and chemotherapeutic resistance. Therefore, the hypothesis of this proposal is that loss of wild type KLF6 and/or increased expression of its alternatively spliced isoform KLF6-SV1, play a central role in the spectrum of PCa development, progression and metastasis. Our goals are to identify the clinicopathologic impact of KLF6 and KLF6-SV1 dysregulation on tumor behaviour and through genetically engineered in vivo models, identify the genetic and proteomic mechanisms underlying these biologic effects on PCa. Therefore, the specific aims of this proposal are: (1) Define the prevalence and clinicopathologic effects of altered KLF6 and KLF6-SV1 expression in PCa development and progression; (2) Investigate the effects of targeted KLF6 and KLF6-SV1 manipulation on prostate development, tumor susceptibility and malignant transformation, and; (3) Define the "KLF6-PCa interactome" - KLF6 and KLF6-SV1 protein-protein interactions critical to tumorigenesis and metastasis.

描述（由申请人提供）：前列腺癌（PCA）是男性癌症死亡的主要原因，并且诊断为稳定增加。在美国，将被诊断出约198,000名男性，今年将死亡32,000人。因此，鉴定前列腺肿瘤开始，生长和转移性差异的病因基因和分子途径代表了改善诊断和预防和治疗策略的基本原理发展的重点。我们证明了肿瘤抑制剂KLF6是调节与生长相关信号转导途径的锌指转录因子家族的成员，在人PCA中经常被灭活。现在有两条证据表明，KLF6状态既可以定义PCA易感性和长期结果。首先，在一项针对3400多名男性的多机构研究中，我们表明，无论疾病的家族史如何，特定的种系KLF6 SNP都会增加PCA的终生风险。该SNP增加了KLF6基因的替代剪接，以产生具有生物活性的，生长促进同工型KLF6-SV1，从而增加了肿瘤细胞的增殖，侵袭和体内肿瘤的生长。其次，多个基因表达研究将KLF6表达与肿瘤复发，临床结局差和化学治疗性降低。因此，该提议的假设是野生型KLF6和/或增加其剪接的同工型KLF6-SV1的表达增加，在PCA发育，进展和转移的范围中起着核心作用。我们的目标是确定KLF6和KLF6-SV1失调对肿瘤行为的临床病理影响，并通过体内模型中的基因设计，确定这些生物学对PCA的遗传和蛋白质组学机制。因此，该提案的具体目的是：（1）定义KLF6和KLF6-SV1表达改变在PCA发育和进展中的患病率和临床病理影响；（2）研究靶向的KLF6和KLF6-SV1操纵对前列腺发育，肿瘤易感性和恶性转化的影响以及；（3）定义“ KLF6-PCA Interactome” - KLF6和KLF6-SV1蛋白 - 蛋白质蛋白相互作用对肿瘤发生和转移至关重要。