Role of the tumor suppressor KLF6 in prostate cancer

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，诊断病例稳步增加。在美国，今年将有约198,000名男性被确诊，32,000人死亡。因此，确定前列腺肿瘤发生、生长和转移扩散的致病基因和分子途径是改进诊断和预防和治疗策略的迫切优先事项。我们发现肿瘤抑制因子KLF6是锌指转录因子kruppel样家族的一员，它调节生长相关的信号转导通路，在人类PCa中经常失活。现在有两种证据表明，KLF6状态既可以决定前列腺癌的易感性，也可以决定长期预后。首先，在一项超过3400名男性的多机构研究中，我们已经表明，一个特定的种系KLF6 SNP，无论家族史如何，都会增加PCa的终生风险。该SNP增加了KLF6基因的选择性剪接，从而产生具有生物活性、促进生长的同种异构体KLF6- sv1，从而增加肿瘤细胞的增殖、侵袭和体内肿瘤生长。其次，多基因表达研究将KLF6表达降低与肿瘤复发、不良临床结局和化疗耐药联系起来。因此，本研究的假设是野生型KLF6的缺失和/或KLF6- sv1的表达增加在PCa的发生、进展和转移中起着核心作用。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，并通过基因工程的体内模型，确定这些生物效应对PCa的遗传和蛋白质组学机制。因此，本提案的具体目的是：(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作用；(2)探讨靶向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-对肿瘤发生和转移至关重要的蛋白相互作用。

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.