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

• 批准号: 7262066
• 负责人: JOHN A MARTIGNETTI
• 金额: $ 32.86万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/7262066
• 关键词: Accounting; Affect; Affinity Chromatography; Alternative Splicing; Behavior; Binding; Cancer Etiology; Cell Proliferation; Cessation of life; Clinical; Complement; Complex; Coupled; Cytoplasmic Protein; Development; Diagnosis; Diagnostic; Disease; Engineering; Event; Family; Family history of; Gene Expression; Gene Silencing; Genes; Genetic; Goals; Growth; Histology; Human Cell Line; Image; Investigation; Link; Localized; Luciferases; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Mus; N-terminal; Neoplasm Metastasis; Nuclear; Outcome; PC3 cell line; Pathway interactions; Play; Predisposition; Prevalence; Prostate; Prostatic Neoplasms; Protein Isoforms; Proteins; Proteomics; RNA Splicing; Range; 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 protein interaction; retroviral-mediated; time use; transcription factor; tumor; tumor growth; tumor initiation; tumorigenesis; tumorigenic

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，诊断病例不断增加。在美国，今年将有约 198,000 名男性被确诊，32,000 人死亡。因此，鉴定前列腺肿瘤发生、生长和转移扩散的致病基因和分子途径是改进诊断以及预防和治疗策略的合理开发的当务之急。我们证明肿瘤抑制因子 KLF6 是调节生长相关信号转导途径的 Kruppel 样锌指转录因子家族的成员，在人类 PCa 中经常失活。现在有两条证据表明 KLF6 状态可以定义 PCa 易感性和长期结果。首先，在一项针对 3,400 多名男性的多机构研究中，我们发现，无论家族病史如何，特定种系 KLF6 SNP 都会增加终生罹患 PCa 的风险。该 SNP 增加了 KLF6 基因的选择性剪接，产生具有生物活性、促进生长的亚型 KLF6-SV1，从而增加肿瘤细胞增殖、侵袭和体内肿瘤生长。其次，多项基因表达研究将 KLF6 表达降低与肿瘤复发、不良临床结果和化疗耐药联系起来。因此，该提议的假设是野生型 KLF6 的缺失和/或其选择性剪接亚型 KLF6-SV1 的表达增加，在 PCa 的发育、进展和转移谱中发挥核心作用。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，并通过基因工程体内模型，确定这些对 PCa 生物学影响的遗传和蛋白质组机制。因此，本提案的具体目标是： (1) 明确 KLF6 和 KLF6-SV1 表达改变在 PCa 发生和进展中的患病率和临床病理学影响； (2) 研究靶向KLF6和KLF6-SV1操作对前列腺发育、肿瘤易感性和恶性转化的影响； (3)定义“KLF6-PCa相互作用组”——KLF6和KLF6-SV1蛋白质-蛋白质相互作用对肿瘤发生和转移至关重要。