Chromatin associated functions of the APC tumor suppressor

APC 肿瘤抑制因子的染色质相关功能

• 批准号: 8796116
• 负责人: William Charles Hankey
• 金额: $ 3.83万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8796116
• 关键词: APC gene; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Adhesions; Affect; American; Apoptosis; Binding; Binding Sites; CTNNB1 gene; Cancer Etiology; Cancerous; Candidate Disease Gene; Cell Culture Techniques; Cell Cycle; Cell Line; Cells; Chromatin; Code; Colon Carcinoma; Colorectal Cancer; Colorectal Polyp; Complex; Consensus; Cytoplasmic Protein; DNA; DNA Binding; DNA Sequence Alteration; Data; Defect; Development; Diagnostic Neoplasm Staging; Differentiation and Growth; Disease; Down-Regulation; Enhancers; Event; Future; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Genetic screening method; Genome; Genomics; Growth; Immunohistochemistry; In Vitro; Informatics; Inherited; Intestines; Large Intestine; Lead; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; MicroRNAs; Multi-Drug Resistance; Mutate; Mutation; Names; Neoplasm Metastasis; Nuclear Protein; Patients; Pharmaceutical Preparations; Polyps; Predisposition; Prevention; Proteins; Proto-Oncogenes; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Severity of illness; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Staging; Syndrome; Testing; Therapeutic Agents; Time; Tissue Microarray; Transcriptional Regulation; Tumor Suppressor Genes; Tumor Suppressor Proteins; Untranslated RNA; Up-Regulation; Western Blotting; angiogenesis; cancer cell; cell growth; chemotherapy; chromatin immunoprecipitation; clinical phenotype; improved; in vivo; knock-down; neoplastic cell; next generation sequencing; novel; novel therapeutics; outcome forecast; public health relevance; research study; therapeutic target; therapy resistant; transcription factor; transcriptome sequencing; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Over a lifetime, roughly 5% of Americans develop colorectal cancer, and more than a third do not survive the disease. Colorectal cancer begins to develop when cells in the lining of the lower intestine suffer genetic mutations that cause growth and proliferation into a colorectal polyp. If not removed, this pre-cancerous growth eventually develops into a malignant tumor. One common type of mutation, found in approximately 80% of colorectal cancers, causes defects the APC protein, named after the inherited syndrome of colon cancer predisposition familial adenomatous polyposis coli. Defects in this protein trigger the formation of a polyp. It is critical to identify how APC deficiency enables a polyp to form and progress into cancer in order to develop new therapeutic strategies for tumor prevention and treatment. Recent studies have shown that APC, a cytoplasmic and nuclear protein with DNA-binding capability, binds an enhancer site upstream of the MYC proto-oncogene, a known Wnt target, to downregulate its transcription directly (Sierra et al., 2006). We hypothesize that APC similarly regulates other targets relevant to tumorigenesis, and that the 80% of colorectal cancers that are deficient in APC may show abnormal activation or suppression of these genes, in comparison to the other 20% of colorectal cancers. This could potentially cause these two groups of cancers to respond differently to chemotherapy, and may help explain why certain therapies benefit some patients but not others. Our preliminary genomic and informatics data show that in colorectal cancer cells with activated Wnt signaling but intact APC, the loss of APC causes abnormal activation or suppression of nearly 200 genes. These proposed studies will identify which of those genes are truly controlled by the interaction of APC with DNA, the mechanism by which APC controls them, and which of them are important for tumor development. Patient tumor samples of different stages and grades will be tested for activation or suppression of these genes. If changes in certain genes are associated with clinical phenotypes, then testing for these changes in patients may lead to more accurate prognosis and improve treatment decisions. Genes activated or suppressed by APC can be targeted by new drugs developed against APC-deficient colorectal cancers.

描述（由申请人提供）：在一生中，大约5%的美国人患上结直肠癌，超过三分之一的人无法在这种疾病中生存。大肠癌开始发展时，细胞在内层的较低的肠道遭受基因突变，导致生长和增殖成结肠直肠息肉。如果不切除，这种癌前生长最终会发展成恶性肿瘤。在大约80%的结直肠癌中发现的一种常见类型的突变导致APC蛋白缺陷，以结肠癌易感性家族性腺瘤性结肠息肉病的遗传综合征命名。这种蛋白质的缺陷会触发息肉的形成。关键是要确定APC缺陷如何使息肉形成， 研究进展，以开发用于肿瘤预防和治疗的新的治疗策略。最近的研究表明，APC（一种具有DNA结合能力的细胞质和核蛋白）结合MYC原癌基因上游的增强子位点（一种已知的Wnt靶标），以直接下调其转录（Sierra et al. 2006年）。我们假设APC类似地调节与肿瘤发生相关的其他靶点，并且与其他20%的结直肠癌相比，APC缺陷的80%的结直肠癌可能显示出这些基因的异常激活或抑制。这可能会导致这两组癌症对化疗的反应不同，并可能有助于解释为什么某些治疗对某些患者有益，而对其他患者则没有。我们的初步基因组和信息学数据显示，在具有激活的Wnt信号但APC完整的结直肠癌细胞中，APC的缺失导致近200个基因的异常激活或抑制。这些拟议的研究将确定这些基因中的哪些是真正由APC与DNA的相互作用控制的，APC控制它们的机制，以及它们中的哪些对肿瘤发展很重要。将测试不同阶段和等级的患者肿瘤样品的这些基因的激活或抑制。如果某些基因的变化与临床表型相关，那么检测患者的这些变化可能会导致更准确的预后并改善治疗决策。APC激活或抑制的基因可以被针对APC缺陷型结直肠癌开发的新药靶向。