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Identification and characterization of genetic regulators in cancer stem cell

癌症干细胞遗传调节因子的鉴定和表征

基本信息

批准号：
7672533
负责人：
Li Cai
金额：
$ 18.01万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7672533
关键词：
Acute Myelocytic Leukemia Binding Sites Breast Breast Cancer Treatment CCL2 gene CD44 gene Cell Line Cells Complex Computer Simulation DNA Methylation DNA Sequence Development Down-Regulation Ectopic Expression Electroporation Epigenetic Process Epithelial Epithelial Cells Functional RNA Gene Expression Genes Genetic Genome Genomics Goals Human In Vitro Knock-out Knowledge Laboratories Lead Malignant Neoplasms Mammary Neoplasms Mammary gland Methods Molecular Molecular Genetics Mouse Cell Line Mutate Mutation NF-kappa B Nature Neoplasm Metastasis Pathway interactions Population Prevention Property Proteins Publishing Reporter Reporter Genes Research Role Somatotropin Stem Cell Development Stem cells TP53 gene Test Result Testing Therapeutic Tissues Trans-Activators Transcriptional Regulation Undifferentiated United States Vertebrates Woman Workload base cancer stem cell cancer therapy cell type chromatin immunoprecipitation comparative expression vector genetic element improved innovation loss of function malignant breast neoplasm mouse model neoplastic cell new therapeutic target novel novel strategies prophylactic public health relevance response stem cell differentiation theories tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Breast cancer stem cells have been identified as CD44?/low breast tumor cells that exclusively retain the ability to form new tumors in mouse models. Cancer stem cells can arise from mutations in normal stem cells directly, or from mutations in progenitor cells that lead to the regaining of stem cell property. Although normally down-regulated during mammary epithelial differentiation, CD44 is expressed in up to 85% human breast cancers and the ectopic expression of CD44 has been shown to promote metastasis. It is possible that the deregulation of CD44 in breast stem cell is associated with tumorigenic transformation due to mutations in pathways that regulate CD44 expression. Therefore it is extremely important to dissect the molecular mechanism(s) that regulates CD44 expression in breast stem cells and controls CD44 down-regulation during stem cell differentiation. Gene expression can be controlled by genetic elements (e.g., cis-regulators, i.e., non- coding DNA sequences that control cell type-specific expression/suppression of genes), in addition to epigenetic controls such as DNA methylation. Due to the highly complex nature of the genome, finding cis-regulators, which determine cell type-specific (stem cells versus differentiated cell) gene expression, in vertebrates remains a difficult task. However, the fact that many cis-regulators are often evolutionarily conserved across species provides a basis for the identification of these cis-regulators using comparative genomic method. Our approach employing in silico predication and "wet lab" verification methods to identify crucial cis-regulators and trans-acting factors of the CD44 gene is highly innovative. Evolutionarily conserved non-coding regions for the prediction of cis-regulators greatly reduced false positives, hence, work load for experimental verification. It provides an integrative way to decode the complicated transcriptional regulation of CD44. Understanding regulatory mechanisms of CD44 expression could ultimately lead to the identification of pathways that could be mutated during the tumorigenic transformation of breast stem cells or cells further down the differentiation hierarchy and thus may provide new therapeutic targets for treatment of breast cancer. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to dissect molecular mechanisms that regulate the expression of the breast cancer stem cell marker CD44 .Understanding regulatory mechanisms of CD44 expression could ultimately lead to the identification of pathways that could be mutated during tumorigenic transformation of breast stem cells or cells further down the differentiation hierarchy and thus provide novel therapeutic targets for treatment of breast cancer, aimed directly at the origin of the tumor.

描述（由申请人提供）：乳腺癌干细胞已被鉴定为CD44β/低乳腺肿瘤细胞，其专门保留在小鼠模型中形成新肿瘤的能力。癌症干细胞可以直接由正常干细胞的突变产生，也可以由祖细胞的突变产生，导致干细胞特性的恢复。尽管在乳腺上皮分化过程中通常下调，但 CD44 在高达 85% 的人类乳腺癌中表达，并且 CD44 的异位表达已被证明可促进转移。由于调节 CD44 表达的途径发生突变，乳腺干细胞中 CD44 的失调可能与致瘤性转化有关。因此，剖析调节乳腺干细胞中 CD44 表达并控制干细胞分化过程中 CD44 下调的分子机制极其重要。除了表观遗传控制（例如DNA甲基化）之外，基因表达还可以通过遗传元件（例如，顺式调节子，即控制细胞类型特异性表达/基因抑制的非编码DNA序列）来控制。由于基因组的高度复杂性，在脊椎动物中寻找决定细胞类型特异性（干细胞与分化细胞）基因表达的顺式调节因子仍然是一项艰巨的任务。然而，许多顺式调节因子在物种间进化上往往是保守的，这一事实为使用比较基因组方法鉴定这些顺式调节因子提供了基础。我们采用计算机预测和“湿实验室”验证方法来识别 CD44 基因的关键顺式调节因子和反式作用因子的方法具有高度创新性。用于预测顺式调节子的进化保守的非编码区域大大减少了误报，因此减少了实验验证的工作量。它提供了一种解码 CD44 复杂转录调控的综合方法。了解 CD44 表达的调节机制最终可能导致乳腺干细胞或分化层次中的细胞在致瘤转化过程中可能发生突变的途径的鉴定，从而可能为乳腺癌的治疗提供新的治疗靶点。公共健康相关性：本提案的目的是剖析调节乳腺癌干细胞标记物 CD44 表达的分子机制。了解 CD44 表达的调节机制可能最终导致确定乳腺干细胞或进一步分化层次的细胞在致瘤转化过程中可能发生突变的途径，从而为乳腺癌的治疗提供新的治疗靶点，直接针对乳腺癌的起源。肿瘤。