Role of the tumor suppressor KLF6 in prostate cancer

描述(申请人提供)：前列腺癌(PCa)是男性癌症死亡的主要原因，确诊病例稳步增加。在美国，今年大约有19.8万名男性被确诊，3.2万人死亡。因此，识别前列腺癌发生、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理论发展的当务之急。我们证明了肿瘤抑制基因KLF6在人类前列腺癌中经常失活，KLF6是锌指转录因子家族中的一员，该家族调节与生长相关的信号转导通路。现在有两条证据表明，KLF6状态既可以决定PCa的易感性，也可以决定长期结果。首先，在一项对3,400多名男性进行的多机构研究中，我们已经表明，特定的生殖系KLF6 SNP，无论其家族病史如何，都会增加终生前列腺癌的风险。这种SNP增加了KLF6基因的选择性剪接，以产生生物活性的、促进生长的亚型KLF6-SV1，它增加了肿瘤细胞的增殖、侵袭和体内的肿瘤生长。第二，多基因表达研究表明KLF6表达降低与肿瘤复发、不良临床结果和化疗耐药有关。因此，这一假设是野生型KLF6缺失和/或其选择性剪接异构体KLF6-SV1表达增加，在前列腺癌的发生、发展和转移过程中起核心作用。我们的目标是确定KLF6和KLF6-SV1基因异常对肿瘤行为的临床病理影响，并通过体内基因工程模型，确定这些生物效应在PCa中的遗传和蛋白质组学机制。因此，本研究的具体目的是：(1)明确KLF6和KLF6-SV1在前列腺癌发生发展中的发生率和临床病理作用；(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-蛋白相互作用对肿瘤的发生和转移至关重要。

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.