Tumor repressive role of Ets2 in the intestine

Ets2在肠道中的肿瘤抑制作用

• 批准号: 8151008
• 负责人: ROBERT GLEN OSHIMA
• 金额: $ 41.13万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8151008
• 关键词: Alleles; Azoxymethane; Behavior; Benign; Biological Assay; Birth; Cell Count; Cells; Chromosomes, Human, Pair 21; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Control Animal; Development; Disease; Endothelial Cells; Epigenetic Process; Epithelium; Family; Fluorescence-Activated Cell Sorting; Genes; Genetic; Genomics; Growth Factor; Homeobox; Human Chromosomes; Intestinal Neoplasms; Intestines; Keratin; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mammary Neoplasms; Measures; Mediating; Mus; Mutation; Oncogenic; Organoids; Pathway interactions; Population; Regulation; Reporter Genes; Risk; Role; Signal Pathway; Signal Transduction; Sodium Dextran Sulfate; Stem cells; TP53 gene; Tamoxifen; Testing; Therapeutic; Therapeutic Intervention; Transgenes; Transgenic Mice; Transplantation; Tumor Stem Cells; Tumor Suppressor Proteins; Undifferentiated; adenoma; base; beta catenin; beta-Galactosidase; cancer stem cell; cellular targeting; colonic crypt; gain of function; in vivo; loss of function; macrophage; member; mouse development; multicatalytic endopeptidase complex; public health relevance; recombinase; red fluorescent protein; research study; self-renewal; transcription factor; trophoblast; tumor; tumor progression; ubiquitin ligase

DESCRIPTION (provided by applicant): Ets2 is one member of the Ets transcription factor family that is essential for mouse development because of a key role in trophoblast stem cells. Ets2 functions in the stromal to support mammary tumors and additionally functions in macrophages and endothelial cells. It is activated by growth factor signaling pathways and contributes to the regulation of Cdx2, a homeobox regulator of both trophoblast and intestinal development. Ets2 has been proposed to be responsible for a repressive role of increased copies of the mouse equivalent of human chromosome 21 on experimental intestinal tumors. Our preliminary results indicate that Ets2 deficiency results in preferential colonization of colonic crypts and an increased rate of crypt fusion. We propose to determine if Ets2 restricts intestinal stem cells and tumor stem cells by inactivating Ets2 genetically and over expressing Ets2 in mice. Loss of function experiments will be performed with conditional alleles of Ets2 and intestinal stem cell specific expression of Cre recombinase. Gain of function experiments will utilize conditional expression of a new transgene driven by the keratin 18 gene and Cre recombinase expressed in intestinal stem cells. These experiments will test the hypothesis that Ets2 decreases sensitivity to intestinal tumors by regulating normal and tumor intestinal stem cells. PUBLIC HEALTH RELEVANCE: If colorectal cancer is a stem cell driven disease, therapeutic strategies to instruct cancer stem cells to differentiate to a benign fate are possible. Understanding the regulation of intestinal stem cells is fundamentally important for evaluating the risk of colon cancer formation and for identifying new strategies for therapeutic intervention.

描述（由申请人提供）：ETS2是ETS转录因子家族的一个成员，它对于小鼠发育至关重要，因为在滋养细胞干细胞中具有关键作用。 ETS2在基质中起作用以支持乳腺肿瘤，并在巨噬细胞和内皮细胞中起作用。它被生长因子信号通路激活，并有助于CDX2的调节，CDX2是滋养细胞和肠道发育的同源蛋白酶调节剂。已经提出ETS2负责增加人类染色体在实验性肠道肿瘤上的小鼠等效副本的抑制作用。我们的初步结果表明，ETS2缺乏会导致结肠隐窝的优先定殖和隐窝融合率的提高。我们建议通过在小鼠中灭活ETS2和过度表达ETS2来确定ETS2是否限制了肠道干细胞和肿瘤干细胞。功能实验的丧失将使用ETS2的条件等位基因和CRE重组酶的肠干特异性表达进行。功能实验的增益将利用由肠道干细胞中表达的角蛋白18基因和CRE重组酶驱动的新转基因的条件表达。这些实验将检验以下假设：ETS2通过调节正常和肿瘤肠道干细胞来降低对肠道肿瘤的敏感性。 公共卫生相关性：如果结直肠癌是一种干细胞驱动的疾病，则可以使用指导癌症干细胞区分良性命运的治疗策略。了解肠道干细胞的调节对于评估结肠癌形成的风险和确定治疗干预的新策略至关重要。