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）：一生中，大约有5％的美国人患上了结直肠癌，而三分之一以上无法生存。当下肠中的细胞遭受遗传突变，导致生长和增殖成结直肠息肉时，结直肠癌开始发展。如果没有去除，这种癌前生长最终会发展为恶性肿瘤。在大约80％的结直肠癌中发现的一种常见的突变类型是导致APC蛋白的缺陷，APC蛋白是以结肠癌遗传综合征术语命名的家族性腺瘤性念珠菌大肠杆菌。该蛋白质中的缺陷会触发息肉的形成。至关重要的是要确定APC缺陷如何使息肉形成和 发展为癌症，以制定用于预防肿瘤和治疗的新治疗策略。最近的研究表明，APC是具有DNA结合能力的细胞质和核蛋白，它结合了MYC原始癌基因上游的增强子位点，即已知的Wnt靶标，以直接下调其转录（Sierra等，2006）。我们假设APC类似地调节与肿瘤发生相关的其他靶标，并且与其他20％的结直肠癌相比，在APC中缺乏APC的80％的结直肠癌可能显示出异常的激活或抑制。这可能会导致这两组癌症对化学疗法的反应有所不同，并可能有助于解释为什么某些疗法使某些患者受益但其他患者受益。我们的初步基因组和信息学数据表明，在具有活化的Wnt信号传导但完整APC的结直肠癌细胞中，APC的丧失会导致异常激活或抑制近200个基因。这些提出的研究将确定哪些基因中的哪些是由APC与DNA的相互作用真正控制的，APC控制它们的机制，哪些对肿瘤的发育很重要。不同阶段和成绩的患者肿瘤样本将被测试以激活或抑制这些基因。如果某些基因的变化与临床表型相关，那么对患者的这些变化进行测试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是针对APC缺陷型结直肠癌的新药物的靶向。